MXPA06003579A

MXPA06003579A - Benzoimidazole compounds

Info

Publication number: MXPA06003579A
Application number: MXPA/A/2006/003579A
Authority: MX
Inventors: Haripada Khatuya; James P Edwards; Michael D Hack; Jennifer D Venable; Kristen L Arienti; J Guy Breitenbucher; Daniel J Buzard; David E Kindrachuk; Alice Lee
Original assignee: Kristen L Arienti; J Guy Breitenbucher; Daniel J Buzard; James P Edwards; Michael D Hack; Haripada Khatuya; David E Kindrachuk; Alice Lee; Jennifer D Venable
Priority date: 2003-09-30
Filing date: 2006-03-30
Publication date: 2007-04-20

Abstract

Benzoimidazole compounds, compositions, and methods of using them in leukocyte recruitment inhibition,in modulating H4 receptor, and in treating conditions such as inflammation, H4 receptor-medidated conditions, and related conditions.

Description

BENZIMIMIDAZOLE COMPOUNDS FIELD OF THE INVENTION The invention relates to novel, pharmaceutically active, fused heterocyclic compounds, very particularly benzoimidazole compounds, and methods for using them to treat or prevent disorders and conditions mediated by the histamine H receptor.

BACKGROUND OF THE INVENTION Histamine was first identified as a hormone (G. Barger and HH Dale, J. Physiol. (London) 1910, 41: 19-59) and has since been shown to play an important role in a variety of physiological processes, including the "triple response" inflammatory through H1 receptors (ASF Ash and HO Schild, Br. J. Pharmac, Chemother, 1966, 27: 427-439), secretion of gastric acid through H2 receptors (JW Black et al. al., Nature 1972, 236: 385-390), and neurotransmitter release in the central nervous system through H3 receptors (J.-M. Arrang et al., Nature 1983, 302: 832-837) (for review see SJ Hill et al., Pharmacol. Rev. 1997, 49 (3): 253-278). It has been shown that the three histamine receptor subtypes are members of the superfamily of G protein-coupled receptors (I. Gantz et al., Proc. Nati, Acad. Sci. USA 1991, 88: 429-433, TW Lovenberg et al. al., Mol.Pharmacol., 1999, 55 (6): 1101-1107; M. Yamashita et al., Proc. Nati, Acad. Sci. USA 1991, 88: 11515-11519). However, there are additional functions of histamine that have been reported, for which no receptor has been identified. For example, in 1994, Raible et al., Showed that histamine and Ra-methylhistamine could activate the mobilization of calcium in human eosinophils (DG Raible et al., Am. J. Respir. Crit. Care Med. 1994, 149: 1506-1511). These responses were blocked by the H3 receptor antagonist thioperamide. However, R-α-methylhistamine was significantly less potent than histamine, which was not consistent with the involvement of the known H3 receptor subtypes. Therefore, Raible et al. they hypothesized the existence of a novel histamine receptor on eosinophils that was non-H-i, non-H2, and non-H3. More recently several groups (T. Oda et al., J. Biol. Chem. 2000, 275 (47): 36781-36786; C. Liu et al., Mol. Pharmacol. 2001, 59 (3): 420-426; T. Nguyen et al., Mol.Pharmacol., 2001, 59 (3): 427-433; Y. Zhu et al., Mol. Pharmacol., 2001, 59 (3): 434-441; KL Morse et al. , J. Pharmacol, Exp. Ther, 2001, 296 (3): 1058-1066) have identified and characterized a fourth subtype of histamine receptor, the H4 receptor. This receptor is a seven-transmembrane G-protein coupled receptor of 390 amino acids with approximately 40% homology to the histamine H3 receptor. Unlike the H receptor, which is located mainly in the brain, the H receptor is expressed at higher levels in eosinophils and mast cells, among other cells, as reported by Liu et al. (see above) and C.L. Hofsíra et al.

(J. Pharmacol. Exp. Ther 2003, 305 (3): 1212-1221). Due to its preferential expression on immunocompetent cells, this H4 receptor is closely related to the regulatory functions of histamine during the immune response. A biological activity of histamine in the context of immunology and autoimmune diseases is closely related to the allergic response and its deleterious effects such as inflammation. Events that induce the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function or a combination of these. The degranulation of mast cells (exocytosis) releases histamine and leads to an inflammatory response that can be initially characterized by a histamine-induced hives and redness reaction. A wide variety of immunological stimuli (v.gr., allergens or antibodies) and non-immunological (eg, chemical) stimuli can cause the activation, recruitment and degranulation of mast cells. The activation of mast cells initiates the allergic inflammatory responses (H-i) that in turn cause the recruitment of other effector cells that also contribute to the inflammatory response. Histamine H2 receptors modulate the secretion of gastric acid and histamine H3 receptors affect the release of neurotransmitters in the central nervous system.

Modulation of H4 receptors controls the release of inflammatory mediators and inhibits the recruitment of leukocytes, thereby providing the ability to prevent and / or treat diseases and conditions measured by H4, including the deleterious effect of allergic responses such as inflammation. The compounds according to the present invention have H4 receptor modulating properties. The compounds according to the present invention have leukocyte recruitment inhibitory properties. The compounds according to the present invention have anti-inflammatory properties. Examples of textbooks on the subject of inflammation include J. I. Gallin and R. Snyderman, Inflammation: Basic Principles and Clinical Correlates, 3rd Edition, (Lippíncott Williams &Wiikins, Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin, "Inflammation and Fever", Pathophysiology Principles of Diseases (Textbook for Medical Students, Academic Press, 1995); Cecil et al., Textbook Of Medicine, 18th Edition (W. B. Saunders Company, 1988); and Steadmans Medical Dictionary. Background and review material on inflammation and conditions related to inflammation can be found in articles such as the following: C. Nathan, Points of control in inflammation, Nature 2002, 420: 846-852; K.J. Tracey, The inflammatory reflex, Nature 2002, 420: 853-859; L.M. Coussens and Z. Werb, Inflammation and Cancer, Nature 2002, 420: 860-867; P. Libby, Inflammation in atherosclerosis, Nature 2002, 420: 868-874; C. Benoist and D. Mathis, Mast cells in autoimmune disease, Nature 2002, 420: 875-878; H.L. Weiner and D.J. Selkoe, Inflammation and therapeutic vaccination, CNS diseases, Nature 2002, 420: 879-884; J. Cohen, The immunopathogenesis of sepsis, Nature 2002, 420: 885-891; D. Steinberg, Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime, Nature Medicine 2002, 8 (11): 1211-1217. Inflammation here refers to the response that develops as a consequence of histamine release, which in turn is caused by at least one stimulus. Examples of said stimuli are immunological stimuli and non-immunological stimuli. The inflammation is due to any of a plurality of conditions such as allergy, asthma, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis) psoriasis, allergic rhinitis, scleroderma, autoimmune thyroid diseases, immuno-mediated diabetes mellitus (also known as type 1) and lupus, which are characterized by excessive or prolonged inflammation at some stage of the disease. Other autoimmune diseases that lead to inflammation include myasthenia gravis, autoimmune neuropathies such as Guillain-Barré, autoimmune uveitis, autoimmune emolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, antiphospholipid syndrome, vasculitis, such as Wegener's granulomatosis, Behcet's disease, dermatitis herpetiformes, pemphigus vulgaris, vitiligo, primary biliary cirrhosis, autoimmune hepatitis, oophoritis and orchitis, autoimmune disease of the adrenal gland, polymyositis, dermatomyositis, spondyloarthropathies, such as ankylosing spondylitis and Sjogren's syndrome. With respect to the onset and evolution of inflammation, inflammatory diseases or diseases or conditions mediated by inflammation include but are not limited to acute inflammation, allergic inflammation and chronic inflammation. The cited references are incorporated herein by reference.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to a compound of the formula (I) or (11): wherein W is, independently of other member and substituent assignments, N or CR7: X is, independently of other member and substituent assignments, N or CH; And it is, independently of other assignments of members and substituents, O, NR12, or CR12R13; Z is, independently of other member and substituent assignments, N or CR14, in which case the solid / dotted line characteristic (_) in any of the formulas (I) and (II) is a single link; or Z is C, in which case the solid / dotted line characteristic (.__-_) in any of the formulas (I) and (II) is a double bond; n is independently of member assignments and substituents, 0, 1, or 2; each of R1"4 is, independently of other allocations of members and substituents, H, C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3.6 cycloalkyl, C? -4 alkoxy, C1.4 alkylamino, C -? - alkylthio, C -? - 4 alkylsulfonyl, C3.6 -cycloalkyl, -OCH2Ph, cyano, -CF3, F, Cl, Br, I, nitro, -OCF3, - SCF3, -OR °, -SRC, -S (0) Rc, -S02Rc, -C (0) Rc, phenyl, benzyl, phenethyl, -C (0) NRaRb, -C (0) ORc, -NRaRb, - CH2NRaRb or -CH2ORc, wherein each of Ra, Rb and Rc is, independently of other assignments of substituents, selected from H, C? -4 alkyl, C3-6 cycloalkyl, phenyl, (C3-6 cycloalkyl) C 2 -2 alkyl, benzion and phenethyl, or Ra and Rb taken together with the nitrogen to which they are attached, form a heterocyclic ring of 4-7 members HetCyd, wherein said ring HetCyd has 0 or 1 additional heteroatoms selected from O, S, > NH " C alkyl-6, and wherein any phenyl, phenethyl, benzyl, alkyl or cycloalkyl moiety ilo in any of said R1"4, Ra, Rb, Rc, and the ring HetCyd is optionally, and independently of other assignments of substituents, substituted with 1, 2 or 3 substituents selected from C? -3 alkyl, halogen, hydroxy , amino, and C1-3 alkoxy; each of R5"7 is, independently of other member and substituent assignments, H, C?-C6 alkyl, F, Cl, Br, I, CF3, -OCF3, -OR °, -alkyl of C?-3ORc , -alkyl of C1-3SR °, -SRC, -S (0) Rc, -S0 Rc, alkoxy of CM, cyano, nitro, -C (0) NRaRb, -NRaRb, -alkyl of C? -3NRaRb, - C (0) phenyl, -C (0) C? -6 alkyl, -S (O) C1-4 alkyl, or -S02C1-4alkyl; or, R5 and R6 for a compound of the formula (I) ) taken together with the carbon atoms to which they are attached form a cyclic structure Cyc1 selected from ary, heteroaryl, 5 or 6 membered carbocycle, and 5 or 6 membered heterocycle with 1 or 2 heteroatoms, wherein said cyclic structure Cyc1 is, independently of other assignments of substituents, substituted with 0, 1, or 2 substituents selected from C 1 -3 alkyl, halogen, hydroxy, amino, and C 1 -C 3 alkoxy; or, R 7 and R 6 for a compound of the formula (II) taken together with the carbon atoms to which they are attached form a structure Cyclic cyclic selected from aryl, heteroaryl, 5- or 6-membered carbocycle and 5- or 6-membered heterocycle with 1 or 2 heteroatoms, wherein said cyclic structure Cyc2 is, independently of other substituent assignments, substituted with 0, 1, or 2 substituents selected from C -? - 3 alkyl, halogen, hydroxy, amino, and C 1-3 alkoxy; R8 is, independently of other assignments of members and substituents, H, C? -6 alkyl, C-M alkoxy, or OH; each of R9 and R10 is, independently of other assignments of members and substituents, H or C? -6 alkyl, or R9 and R10 taken together form a cyclic structure of 5-6 Cyc3 members, wherein said Cyc3 cyclic structure is a carbocycle of 5 or 6 members or a heterocycle of 5 or 6 members with 1 or 2 heteroatoms, and wherein said cyclic structure Cyc3 is, independently of other alloy assignments, substituted with 0, 1 or 2 substituents selected from C-alkyl -? - 3, halogen, hydroxy, amino, and Ci ^ alkoxy; R11 is, independently of other member assignments and substituents, H or C? -4 alkyl; each of R12 and R13 is, independently of other assignments of members and substituents, H or C1-4 alkyl; or, when Y is CR12R13, R12 and R13 taken together with the carbon member to which they are attached form an optionally substituted cyclic structure Cyc4, wherein said cyclic structure Cyc4 is a 3-6 membered carbocycle or a 3-6 heterocycle members with 0 or 1 additional heteroatoms, or CR12R13 is C = 0; R 14 is, independently of other assignments of members and substituents, H, C 1-4 alkyl, OH, or C 1-4 alkoxy; an enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt, amide or ester thereof; with the following conditions: when Y is O or NR12, then Z is CR14 and R8 is not OH or C1.4 alkoxy; when Z is N, Y is CR12R13; and none of R1"4 is C (0) NH2.Isomeric forms of the compounds of formulas (I) and (II), and their pharmaceutically acceptable salts, amides and esters, are encompassed within the present invention, and reference herein to one of said isomeric forms refers to at least one of said isomeric forms, One skilled in the art will recognize that the compounds according to the invention may exist, for example, in an individual isomeric form while other compounds may exist in the form of a regioisomeric mixture Whether or not it is explicitly stated elsewhere in the written description and claims, it is understood that each assignment of substituent and member in the context of this invention is made independently of any other member assignment and substituent, unless otherwise indicated In a manner of a first example on terminology of substituents, if substituent S1empty is one of S -i and S2, and the substitute S2ejempio is one of S3 and S4, then these assignments refer to embodiments of this invention given in accordance with the example choices is 1 and S example is 3; example is i and S example is; S1eje pio is S2 and S2 mpio is S3; S1ejemPio is S2 and S2ejemio is S4; and equivalents of each of said elections. The shorter terminology "S1exempio is one of Si and S2, and S2ejemio is one of S3 and S4" is therefore used here for brevity purposes, but not by way of limitation. The first example above on substituent terminology, which is indicated in generic terms, is understood to illustrate the various substituent assignments R described herein. The above convention given here for substituents extends, when applicable, to members such as X, Y, Z, and W, and the index n. In addition, when more than one assignment is given to any member or substituent, the modalities of this invention comprise the various groupings that can be made from the listed, independently taken and equivalent assignments of the same. As a second example or terminology of substituents, if it is described herein that the substituent S mpio is one of S-i, S2 and S3, this list refers to embodiments of this invention for which Snap is Si; Sej is S2; Sejempio is S3; Sejempio is one of Si and S2; Sejempio is one of Si and S3; Sechem io is one of S2 and S3; Sßjβmpio is one of S1 f S2 and S3; and Sechem io is any equivalent of each of these elections. The shorter terminology "Sejempio is one of Si, S2, and S3" is therefore used here for brevity purposes, but not by way of limitation. The second above example on terminology of substituents, which is indicated in generic terms, means to illustrate the various assignments of substituent R described herein. The above convention given here for substituents extends, when applicable, to members such as X, Y, Z, and W, and to the index n. The nomenclature "C¡.j" with j > i, when applied herein to a class of substituents, it is understood that it refers to embodiments of this invention for which each and every carbon number and member, from i to j including i and j, is carried out. By way of example, the term C. 3 independently refers to embodiments having a carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3). When any variable referring to a substituent, member of the compound or index, occurs more than once, it is understood that the full range of assignments applies to each occurrence, regardless of the specific assignment (s) to any another occurrence of said variable. In accordance with the previous interpretative considerations on assignments and nomenclature, it is understood that the explicit reference here to a set implies, where it is chemically significant and unless otherwise indicated, the independent reference to modalities of said set, and references to each and every possible modality of subsets of the set referred to for clarity purposes. The invention also relates to a pharmaceutical composition for treating or preventing a condition mediated by H 4 receptor in a subject, comprising a therapeutically effective amount of at least one H receptor modulator selected from compounds of the formulas (I), and (11), enantiomers, distereomers, racemates thereof, pharmaceutically acceptable salts, amides, and esters thereof. Furthermore, the invention relates to a pharmaceutical composition for inhibiting leukocyte recruitment in a subject, comprising a therapeutically effective amount of at least one leukocyte recruitment inhibitor selected from compounds of formulas (I) and (11), enantiomers. , diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. The invention further relates to an anti-inflammatory composition, comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. The invention relates to methods of treating or preventing inflammation in a subject, which comprises administering to the subject in connection with an inflammatory response a pharmaceutical composition comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of the formulas (I ) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. The invention also relates to methods for treating or preventing a condition mediated by a H 4 receptor in a subject, which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one H 4 receptor modulator selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. In addition, the invention relates to methods for modulating an H 4 receptor, which comprises exposing an H 4 receptor to at least one compound selected from compounds of formulas (I) and (II), enantiomers, diastereomers, racemates thereof , pharmaceutically acceptable salts, amides and esters thereof. In addition, the invention relates to methods for inhibiting the recruitment of leukocytes in a subject, which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one leukocyte recruitment inhibitor selected from compounds of the formulas ( I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof, pharmaceutical compositions containing at least one of said compounds, methods of use, including and / or prevention of conditions such as those that are mediated by H 4 receptor, and methods for making said pharmaceutical compositions. The following terms are defined below, and for their use throughout the description. "Alkyl" includes straight and branched chain hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, etc. Alkyl does not include cycloalkyl. "Alkenyl" includes straight and branched chain hydrocarbon radicals as above with at least one carbon-carbon double bond (sp2). Unless otherwise indicated, by the prefix indicating the number of carbon members, the alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or -methyl vinyl), but-1-enyl, but-2-enyl, butadienyl, pentenyl, hexa-2,4-dienyl, etc. "Alkynyl" includes straight and branched chain hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Unless indicated otherwise, by the prefix indicating the number of carbon members, the alkynyl include ethynyl, propynyl, butynyl and pentynyl. The hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyl here. "Alkoxy" includes a straight or branched chain group with a terminal oxygen that links the alkyl group with the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, ispropoxy, butoxy, t-butoxy, pentoxy, etc. "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and S02. Unless indicated otherwise, by the prefix indicating the number of carbon members, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Unless indicated otherwise by the prefix indicating the number of members in the cyclic structure, "heterocyclyl", "heterocyclic" or "heterocycle" is a single or fused aromatic, saturated or partially saturated 3-ring system 8 members comprising carbon atoms wherein the carbon atoms are selected from N, O, and S. Examples of heterocyclyls include thiazolyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl. , pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino and most preferably piperidyl. "Carbocycle" is a partially saturated cycloalkyl or cycloalkyl which is not benzo (CT) "Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, etc., any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system can be bicyclic, bridged and / or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentanyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, etc. Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl. . "Halogen" includes fluorine, chlorine, bromine and iodine and is preferably fluorine or chlorine. As in the standard chemical nomenclature, the phenyl group is referred to herein as "phenyl" or as "Ph". "Patient" or "subject" includes mammals such as humans and animals (e.g., dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experimentation, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient is a human being. "Composition" includes a product that comprises the specified ingredients in the specified amounts, including in the effective amounts, as well as any product that results directly or indirectly from combinations of the specified ingredients in the specified amounts. "Therapeutically effective amount" or "effective amount" and grammatically related terms means that amount of active compound or pharmaceutical agent that induces the biological or medicinal response in a tissue, animal or human system that is being sought by a researcher, veterinarian, physician or another clinician, which includes relief of the symptoms of disease or disorder that is being treated.

PICTURE OF ACRONYMS Particular preferred compounds of the invention comprise a benzoimidazole compound of the formula (I) or (II), or an enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt, amide or ester thereof, wherein R1"14 , X, Y, Z, W, and n have any of the meanings defined above and equivalents thereof, or at least one of the following assignments and equivalents thereof, Such assignments may be used where appropriate with any of the definitions, claims or embodiments defined herein: Preferably, W is N or CR7 Preferably, X is N or CH, Preferably, Y is CR12R13, Most preferably, Y is CH2, Preferably, Z is N or CH, Preferably, n = 1 or 2. Most preferably, n = 1. Preferably, R1 is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, F, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido, or CH2OMe. preferable nte, R1 is H, methyl, F, or Cl. Preferably, R2 is independently selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, CF3, OCF3, F, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido, or benzoyl. Most preferably, R2 is H, F, Cl, methyl, CF3, OCF3, or t-butyl. Preferably, R3 is independently selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, CF3, OCF3, F, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido, or benzoyl.

Most preferably, R3 is H, F, Cl, methyl, CF3, OCF3, or t-butyl. Preferably, R 4 is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, R, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido, or CH 2 OMe. Most preferably, R 4 is H, methyl, F, or Cl. Most preferably, one or two of R 1"4 are not H. Preferably, R 5 is H, F, Cl, methyl, or ethyl .. Most preferably, R 5 is F, Cl, methyl, hydroxymethyl, hydroxyethyl, pyrrolidinylmethyl, or diethylaminomethyl, Most preferably, R6 is H, F, Cl, or methyl, Most preferably, R7 is H, F, Cl, or methyl, Most preferably, R5 is Cl, methyl, or hydroxymethyl, preferably R8 is H, methyl, or OH, most preferably, R8 is H. Preferably, R9 and R10 are independently selected from the group consisting of a) H, b) methyl, ethyl, propyl, isopropyl, and c) trifluoromethyl ...} Most preferably, R9 and R10 are, independently, H or methyl Preferably, R11 is H, methyl, or ethyl .. Most preferably, R11 is methyl.

The compounds of the formula (I) or (II) also comprise compounds that satisfy any of the combinations of definitions given herein and equivalents thereof. It is understood that some compounds referred to herein are chiral and / or have geometric isomeric centers, for example E and Z isomers. The present invention encompasses all such optical isomers, including diastereoisomers and racemic mixtures, and geometric isomers possessing the activity that characterizes the compounds of this invention. In addition, certain compounds referred to herein may exist in solvated as well as unsolvated forms. It is understood that this invention encompasses all those solvated and unsolvated forms that possess the activity that characterizes the compounds of this invention. Compounds according to the present invention that have been modified to be detectable by some analytical technique are also within the scope of this invention. An example of such compounds is an isotopically-labeled compound such as an isotopically-labeled compound with 18F that can be used as a probe in detection and / or matrix formation techniques, such as positron emission tomography (PET) and tomography. computerized by single photon emission (SPECT). Another example of such compounds is an isotopically-labeled compound, such as a compound labeled with deuterium and / or tritium that can be used in reaction kinetics studies. It is understood that the substitutions and combinations of substitutions mentioned herein, whether explicitly indicated or not, refer to substitutions that are consistent with the valence of the member being replaced. For example, a substitution applied to a carbon member refers to the tetravalency of C; refers to the trivalency of N when applied to a nitrogen member; and refers to the tetravalence of a nitrogen member that is conventionally characterized with a positive electric charge. The valence options allowed are part of the scope of the technique. The "pharmaceutically acceptable salts, amides and / or esters thereof" refer to those salts, amides and ester forms of the compounds of the present invention that would be apparent to the pharmaceutical chemist, ie, those which are non-toxic and which would favorably affect the pharmacological properties of said compounds of the present invention. Those compounds that have favorable pharmacological properties would be evident to the pharmaceutical chemist, ie, those who are non-toxic and who possess such pharmacological properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, of a more practical nature, which are also important in the selection are costs of the starting materials, ease of crystallization, yield, stability, hygroscopic character and flowability of the resulting bulk drug. Representative acids and bases that can be used in the preparation of pharmaceutically acceptable salts include the following: acids include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) - camphoric acid, camphorsulfonic acid, (+) - (1S) -alphafor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid , cyclamic acid, dodecyl sulfuric acid, ethane-1,2-d-sulphonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactharic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-acid -glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+) - L-lactic acid, (±) -DL-lactic acid or, lactobionic acid, maleic acid, (-) - L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-di-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, oratic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid , stearic acid, succinic acid, sulfuric acid, tannic acid, (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases include ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole , L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazm, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

See, for example, S.M. Berge, et al., "Pharmaceutical Salts", J.

Pharm. Sci. 1977, 66: 1-19, which is incorporated herein by reference. Examples of suitable esters include C 1-7 alkyl, C 5-7 cycloalkyl, phenyl, substituted phenyl and phenyl C 1-6 alkyl esters. Preferred esters include methyl esters. The present invention includes within its scope prodrugs of the compounds of this invention. In general, said prodrugs will be functional derivatives of the compounds that are readily convertible in vivo to the required compound. Therefore, in the methods of treatment of the present invention, the term "administer" will encompass the treatment of the various disorders described with the specifically described compound or with a compound that may not be specifically described, but is converted to the specified compound in vivo after administration to the patient. Similarly, the term "compound", when applied to compounds within the scope of this invention, will encompass in addition to a specific compound of the formula (I) or (II), a compound (or prodrug) that is specifically converted to the compound. described in vivo after administration, even if said prodrug is not explicitly described herein. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elservier, 1985. Compounds where W is CR7 were made in accordance with the synthesis methods delineated in schemes 1 and 2 and examples of said compounds are provided in the group: Example Compound 1 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4,5-dimethyl-1H-benzoimidazole; 2 2-. { 2-Chloro-4- [3- (1-methyl-piperdin-4-yl) -propoxy] -phenyl} -4-methyI-1 H-benzoimidazole; 3 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5- trifluoromethoxy-1 H-benzoimidazole; 4 5-fer-Butyl-2-. { 3-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Fer-Butyl-2-. { 3-Chloro-4- [3- (4-methyl-p-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 6 4,5-Dimethyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 / - / - benzoimidazole; 7-Ier-Butyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 8 5-yer-Butyl-2-. { 3- [4- (4-methy1- [1,4] diazepan-1-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 9 (1 - { 3- [4- (5-Fer-Butyl-1 H-benzoimidazol-2-yl) -2-chloro-phenoxy] -propyl.} - pyrrolidin-3-yl) -dimethylamine; 10 5-Chloro-2-. { 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} - 6-methyl-1 H-benzoimidazole; 11 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 12 5-Methyl-2-. { 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -naphthalene-1-yl} -1 H- benzoimidazole; 13 4- [3- (5-Ier-Butyl-1 H -benzoimidazol-2-yl) -phenoxy] -1- (4-methyl-p-piperazin-1-yl) -butan-1 -one; 14 5-Chloro-2- [3-chloro-4- (3-piperazin-1-yl-propoxy) -phenyl] -6-fluoro-1 H-benzoimidazole; 15 5-fer-Butyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 16 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} 4,6-dimethyl-1 H-benzoimidazole; 17 2-. { 2-Chloro-4- [2-methyl-3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -17-methyl-1 H-benzoimidazole; 18 5-Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6- methyl-1 H-benzoimidazole; 19 6-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4- methyl-1 H-benzoimidazole; 0 5-fe / - Butyl-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 1 5-Chloro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 2 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4,6- dimethyl-1 H-benzoimidazole; 23 5-Chloro-6-methyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 24 5-Chloro-6-fluoro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 25 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1 -i!) - propoxy] -pheni !} -5-methyl-1 H- benzoimidazole; 26 5.6-DifIuoro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 27 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -pheni} -1 H- benzoimidazole; 28 2-. { 2-Chloro-4- [3- (4-methyl) - [1.4] diazepan-1-yl) -propoxij-feni)} -4,5- dimethyl-1 H-benzoimidazole; 29 5,6-Dimethyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 30 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} 4,6-dimethyl-1 H-benzoimidazole; 31 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1H-benzoimidazole; 32 5-Ier-Butyl-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1H-benzoimidazole; 33 2-. { 3-Methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5- trifluoromethyl-1 H-benzoimidazole; 34 5-Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6- fluoro-1 H-benzoimidazole; 35 5,6-Dichloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 36 5-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 37 5-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6- fluoro-1 H-benzoimidazole; 38 5-Chloro-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 39 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methyl-1 H-benzoimidazole; 40 5,6-Dichloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 41 5-Chloro-6-methyl-2-. { 3-methyl-4- [3- (4-methyl-p¡perazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 42 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methyl-1 H-benzoimidazole; 43 5-Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 44 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5- trifluoromethyl-1 H-benzoimidazole; 45 5-Chloro-6-fluoro-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 46 5-Methyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 47 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 48 2-. { 3-Methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -fenii} -1 H- benzoimidazole; 49 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 50 5-Chloro-6-fluoro-2-. { 3-methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy-J-phenyl} -1 H-benzoimidazole; 51 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methoxy-1H-benzoimidazole; 52 5-fer-Butyl-2-. { 3,5-dibromo-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 53 2-. { 2-Methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5- trifluoromethyl-1 H-benzoimidazole; 54 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5- trifluoromethyl-1 H-benzoimidazole; 55 2-. { 3- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 56 (2- {3- [4- (4-Methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H -benzoimidazol-5-yl) -phenyl-methanone; 57 6-Chloro-2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4- methyl-1 H-benzoimidazole; 5-fer-Butyl-2-. { 3-chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy-phenyl} - 1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (1-methyl-p -peridin-4-yl) -propoxy] -phenyl} -4,5-dimethyl-1 H-benzoimidazole; 5-CIOR-6-methyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1H-benzoimidazole; 5-Chloro-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propox-phenyl} -1H-benzoimidazole; 5-Chloro-6-fluoro-2-. { 4- [3- (1-metii-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Ier-Butyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Methyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 4- [3- (1-Methyl-piperidin-4-ii) -propoxy] -phenyl} -1 H-benzoimidazole; 6-Chloro-2-. { 2-fluoro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 5-Fluoro-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 4-Chloro-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 6-Chloro-4-methyl-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 70 5-Chloro-2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -6- fluoro-1 H-benzoimidazole; 71 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -3H-naphtho [1,2-djimidazole; 72 4.6-DimetiI-2-. { 2-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1H-benzoimidazoI; 73 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 74 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-fluoro-4-methyl-1 H-benzoimidazole; 75 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -3H- naphtho [1,2-d] imidazole; 76 6-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5H- [1, 3] dioxolo [4 ', 5': 4,5] benzo [1,2-d] imidazole; 77 6-Chloro-2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} - 4-methyl-1 H-benzoimidazole; 78 2-. { 3-Chloro-4- [3- (4-methyl-1, 4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 79 4,6-Dimethyl-2-. { 3- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -phenyl} -1H- benzoimidazole; 80 5-Chloro-2-. { 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole; 81 2-. { 4- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 82 { 2- (6-Chloro-4-methyl-1 H-benzoimidazol-2-yl) -5- [3- (1-meth yl-piperidin-4-yl) -propoxy] -benzyl} dimethyl amine; 83 { 2- (5-Fluoro-4-methyl-1 H -benzoimidazol-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzyl} dimethyl amine; 84 4-. { 3- [4- (6-Chloro-4-methyl-1H-benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} - [1, 4] diazepan-5-one; 85 4-. { 3- [4- (5-Fer-Butyl-1H-benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} - 1-methyl- [1,4] diazepan-5-one; 86 5-fer-Butyl-2-. { 2-methyl-4- [3- (2-methyl-p-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 87 5-fer-Butyl-2-. { 2-methyl-4- [3- (2-methyl-piperazin-1-yl) -propoxy] -phenyl} - 1 H-benzoimidazole; 88 6-Chloro-4-methyl-2- [2-methyl-4- (3-piperidin-4-yl-propoxy) -phenyl] -1H-benzoimidazole; 89 5-Fluoro-4-methyl-2- [2-methyl-4- (3-piperidin-4-yl-propoxy) -phenyl] -1H-benzoimidazole; 90 6-Chloro-2-. { 4- [3- (1-ethyl-piperidin-4-yl) -propoxy] -2-methyl-phenyl} -4-methyl-1 H-benzoimidazole; 91 { 2- [3-Chloro-4- (4-methyl-1 H-benzoimidazol-2-yl) -phenoxy] -ethyl} -methyl- (1-methyl-piperidin-4-yl) -amine; 92 6-Chloro-4-methyl-2-. { 2-methyl-4- [2- (1-methyl-piperidin-4-yloxy) -ethoxy] -phenyl} -1 H-benzoimidazole; 93 6-Chloro-4-methyl-2-. { 2-methyl-4- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 94 5-Fluoro-4-methyl-2-. { 2-methyl-4- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 95 6-Fluoro-7-methyl-2-. { 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 96 7-Methyl-2-. { 3- [4- (1-methyl-p.peridin-4-yl) -butoxy] -phenyl} -1H- benzoimidazole; 97 6,7-Dimethyl-2-. { 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 98 5-Chloro-7-methyl-2-. { 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 99 5,7-Dimethyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H- benzoimidazole; 100 5-Chloro-7-methyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 101 6-Fluoro-7-methyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 102 6-Fluoro-7-metii-2-. { 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy] -phenyl} - 1 H-benzoimidazole; and 176. { 2- (5-Fluoro-4-methyl-1 H -benzoimidazoI-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -methanol. The compounds wherein W is N were made in accordance with the synthesis methods delineated in schemes 1 to 6 and examples of these compounds are provided in the group: Example Compound 103 6-Chloro-4-methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy) -pyridin-3-yl} -1 H-benzoimidazole; 104 4-Methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1 H- benzoimidazole; 105 5-Fluoro-4-methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 106 4-Methyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H- benzoimidazole; 107 4,5-Dimethyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H- benzoimidazole; 108 4-Chloro-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] pyridin-3-yl} -1H- benzoimidazole; 109 6-Chloro-4-methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 110 4-Methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} - 1H-benzoimitazoi; 11 5-Fluoro-4-methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-ii) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 12-Dimethyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 113 4.6-Dimethyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 114 4-Chloro-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} - 1 H-benzoimidazole; 115 2-. { 4-Chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -5- fluoro-4-methyl-1 H-benzoimidazole; 116 2-. { 4-Cioro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1 H-benzoimidazole; 117 6-Chloro-2-. { 4-chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} - 4-methyl-1 H-benzoimidazole; 118 2-. { 4-Chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4,6- dimethyl-1 H-benzoimidazole; 119 2-. { 4-Methoxy-6- [3- (1-methyl-p-peridin-4-yl) -propoxy] -pyridin-3-yl} -4- methyl-1 H-benzoimidazole; 120 5-Fluoro-2-. { 4-methoxy-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1 H-benzoimidazole; 121 5-Fluoro-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 122 4-Methyl-2-. { 6- [3- (1-methyl-1 ^ .Sd-tetrahydro-pyridin ^ -i -propoxy] -pyridin-3-yl.} -1 H-benzoimidazole; 123 6-Chloro-4-methyl-2 {.6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1-H-benzoimidazole; 124 4,5-Dimethyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 125 4,6-Dimethyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 126 5-Chloro-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 127 5-Fluoro-4-methyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -4-pyrrolidin-1-ylmethyl-pyridin-3-yl} -1 H-benzoimidazole; 128 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-methyl-1 H-benzoimidazole; 129 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5- fluoro-4-methyl-1 H-benzoimidazole; 130 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -6-chloro-4-methyI-1 H-benzoimidazole; 131 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,6- dimethyl-1 H-benzoimidazole; 132 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5- dimethyl-1 H-benzoimidazole; 133 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-4-methyl-1 H-benzoimidazole; 134 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-Ier-butyl-1 H-benzoimidazole; 135 5-fer-Butyl-2-. { 2- [4- (1-methyl-p -peridin-4-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 136 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-fluoro-4-methyl-1 H-benzoimidazole; 137 2-. { 5-Chloro-2- [4- (1-methyi-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5- dimethyl-1 H-benzoimidazo !; 138 4.6-Dimethyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 139 4-Methyl-2-. { 2- [4- (4-methyl-piperazin-1 -i!) - butoxy] -pyridin-4-ii} -1 H- benzoimidazole; 140 4,5-Dimethyl-2-. { 2- [4- (4-Methy1-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole; 141 5-Fluoro-4-methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 142 6-Chloro-4-methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 143 5-Fluoro-4-methyl-2-. { 2- [4- (4-methiI- [1,4] diazepan-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 44 4,5-Dimethyl-2-. { 2- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 145 4,6-Dimethyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 146 4-Methyl-2-. { 2- [4- (1-methyl-p-peridin-4-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 147 5-Fluoro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 148 4-Chloro-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 149 4.5-Dimeti! -2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 150 6-Chloro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} - 1H-benzoimidazoI; 151 5-Chloro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 152-5-Fer-Butyl-2- [2- (4-piperidin-4-yl-butoxy) -pyridin-4-yl] -1H-benzoimidazole; 153 4,6-Dimethyl-2- [2- (4-pyridin-4-yl-butoxy) -pyridin-4-yl] -1H-benzoimidazole; 154 2-. { 2- [4- (1-Ethyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1H-benzoimidazole; 155 4,6-Dimethyl-2-. { 3-methyl-2- [4- (1-methyl-p-peridin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 156 4-Methyl-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 157 6-Chloro-4-methyl-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 158 2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl-butoxy] -pyridin-4-yl.} -4-methyl-1 H-benzoimidazole; 159 2-. {3-Chloro -2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1H-benzoimidazole; 160 4-Chloro-2-. {3-Chloro-2- [4- (1-methyl-piperidin-4-ii) -butoxy] -pyridin-4-yl.} - 1 H-benzoimidazole; 161 2-3-Chloro- 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} - 5-fluoro-4-methyl-1 H-benzoimidazole; 162 2-. Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-6-dimethyl-1H-benzoimidazole; 163 6-Chloro- 2- { 3-chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} - 4-methyl-1 H-benzoimidazole; Chloro-2- {3-chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} - 4-methyl-1 H-benzoimidazole; 165 5-Fluoro-4-methyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 166 5-Chloro-6-fluoro-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 167 5-fer-Butyl-2-. { 5-methyl-2- [4- (1-methyl-p-peridn-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 168 4,5-Dimethyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 169 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,6- dimethyl-1 H-benzoimidazole; 170 5-Chloro-2-. { 5-chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} - 1 H-benzoimidazole; 171 5-Chloro-2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} - 6-fluoro-1 H-benzoimidazole; 172 5-fet-Butyl-2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 173 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-chloro-1 H-benzoimidazole; 174 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-6-fluoro-1 H-benzoimidazole; 175 2-. { 5-Bromo-2-. { 4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-1H-benzoimidazoI; and 177. { 4- (4,6-Dimethyl-1 H-benzoimidazol-2-yl) -6- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-3-yl} -methanol. Modes of pharmaceutical compositions and methods of using compounds according to this invention are provided by pharmaceutical compositions comprising, and by methods of using any of the compounds described herein and combinations thereof. Modalities of pharmaceutical compositions for treating or preventing a condition mediated by H 4 receptor in a subject comprising a therapeutically effective amount of at least one H 4 receptor modulator selected from compounds of formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof, further comprise a pharmaceutically acceptable carrier. Modalities of pharmaceutical compositions for inhibiting the recruitment of leukocytes in a subject comprising a therapeutically effective amount of at least one leukocyte recruitment inhibitor selected from compounds of formulas (I) and (II), enantiomers, diastereomers, racemates of the same, pharmaceutically acceptable salts, amides and esters thereof, further comprise a pharmaceutically acceptable carrier. Modalities of anti-inflammatory compositions comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof , they further comprise a pharmaceutically acceptable carrier. Modes of methods for treating or preventing inflammation in a subject comprising administering to the subject in connection with an inflammatory response a pharmaceutical composition comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of formulas (1) and ( II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof, include methods wherein said inflammatory response is a response to at least one of the conditions: inflammatory disorders, allergic disorders, dermatological disorders , autoimmune diseases, lymphatic disorders, skin itching and immunodeficiency disorders. Modes of methods of treating or preventing inflammation in a subject comprising administering to the subject in connection with an inflammatory response a pharmaceutical composition comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of the formulas (I) and ( II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof, include methods wherein said inflammatory response is a response to chemotherapy. Modalities of methods of treating or preventing inflammation in a subject comprising administering to the subject in connection with an inflammatory response a pharmaceutical composition comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of formulas (I) and ( 11), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof, include methods wherein at least one of the following is satisfied: said inflammatory response is a response to a physical stimulus; said inflammatory response is a response to a chemical stimulus; said inflammatory response is a response to infection; said inflammatory response is a response to an invasion by a body that is foreign to the subject; said inflammatory response is a response to an immunological stimulus; said inflammatory response is a response to a non-immunological stimulus; said inflammatory response is a response to at least one of the conditions: allergy, asthma, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and very specifically wherein said inflammatory bowel disease is caused by at least one of Crohn's disease and ulcerative colitis, psoriasis, allergic rhinitis, scleroderma, autoimmune thyroid disease, immune-mediated diabetes mellitus, and lupus; said inflammatory response is a response to at least one of the conditions: myasthenia gravis, autoimmune neuropathy and very specifically wherein said autoimmune neuropathy is Guillain-Barré neuropathy, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis , anti-phospholipid syndrome, vasculitis, and very specifically where said vasculitis is Wegener's granulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, primary biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis, autoimmune orchitis, autoimmune disease of the gland adrenal, polymyositis, dermatomyositis, spondyloarthropathy, and very specifically wherein said spondyloarthropathy is ankylosing spondylitis, and Sjogren's syndrome; said inflammatory response is acute inflammation; said inflammatory response is allergic inflammation; and said inflammatory response is chronic inflammation. Administration in connection with an inflammatory response in accordance with the present invention includes administration at a time that is at least one of before, at the onset of, and after inflammation is detected. Modes of methods for modulating an H4 receptor comprising exposing an H4 receptor to at least one compound selected from compounds of formulas (I) and (II), enantiomers, diastereomers, racemates thereof, salts, amides and esters pharmaceutically acceptable thereof, include methods wherein at least one of the following is satisfied: at least one compound modulates the H4 receptor as a receptor antagonist, and at least one compound modulates the H4 receptor as an agonist partial receiver. If more than one active agent is administered, such as a compound of the formula (I) or (II), the therapeutically effective amount must be a jointly effective amount. An illustration of the invention is a pharmaceutical composition made by mixing at least one benzoimidazole compound selected from compounds of the formulas (1) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters of the same, and a pharmaceutically acceptable vehicle. The invention is illustrated by a process for making a pharmaceutical composition comprising mixing at least one benzoimidazole compound selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, salts, amides and esters pharmaceutically acceptable thereof, and a pharmaceutically acceptable carrier. Another example of the invention is the use of a composition comprising at least one benzoimidazole compound selected from compounds of the formulas (I) and (11), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters of them, in the preparation of a medicament to treat any of the conditions referred to herein; One of these conditions is inflammation. Another example of the invention is the use of a composition comprising at least one benzoimidazole compound selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, salts, amides and esters pharmaceutically acceptable to them, in the treatment or prevention of any of the conditions referred to herein; One of these conditions is inflammation. The compounds according to the present invention can be made in accordance with processes within the scope of the art and / or in accordance with methods of this invention, such as those described in the schemes and examples which follow and by matrix methods. or combinatorial. To obtain the various compounds herein, starting materials carrying the generally desired substituents can be used through the reaction scheme with or without protection as appropriate. The starting materials can be obtained from commercial sources or can be synthesized by methods known to one skilled in the art. Alternatively, it may be necessary to use, instead of the ultimately desired substituent, a suitable group, which can be carried through the reaction scheme and replaced as appropriate with the desired substituent. Any product containing a chiral center can be separated into its enantiomers by conventional techniques. Those skilled in the art will be able to modify and adapt the guidance provided herein to make compounds in accordance with the present invention. Modes of procedures illustrated herein include, when they have chemical meaning, one or more steps such as hydrolysis, halogenation, protection and deprotection. These steps can be implemented in light of the teachings provided here and the scope of the technique. During any of the methods for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules in question. In addition, the compounds of the invention can be modified using protecting groups; said compounds, precursors or prodrugs are also within the scope of the invention. This can be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3a. ed., John Wiley & Sons, 1999. Protective groups can be removed in a convenient subsequent step using methods known in the art. SCHEME 1 SCHEME 2 Referring to schemes 1 and 2, the following notes and additions are described. The starting materials of the steps described below with respect to schemes 1 and 2 are commercially available or readily accessible to those skilled in the art. The compounds of the formula (I) or (II) are prepared by condensation of an appropriately substituted diaminobenzene (III) under oxidation conditions with an appropriately substituted benzaldehyde (IV) or (IV ") to form a compound of the formula (I) ) when the benzaldehyde (IV) has an ether substitution for the aldehyde group (scheme 1), or a compound of the formula (II) when the benzaldehyde (IV) has a substitution of the metal ether with respect to the aldehyde group ( Scheme 2) Oxidizers suitable for this step include air, Na2S205, oxone, and chemically compatible oxidants having similar oxidizing power and mixtures thereof This condensation is preferably carried out in a medium heated in a chemically compatible solvent The temperatures of the reaction medium preferably range from about 40 ° C to about 150 ° C, most preferably from about 80 ° C to about 100 ° C. e can be used for this reaction include dioxane, THF, benzotrifluoride, toluene, 1,2-dichloroethane, DMA, and DMSO, preferably DMF and mixtures thereof. The suitably substituted benzaldehydes (IV) and (IV ") can be prepared according to procedures known in the art In a preparation process, a suitably substituted hydroxybenzalphe hyde is reacted with an appropriately substituted portion to form the ether linkage in the compounds (IV) and (IV) The reaction with suitably substituted 4-hydroxybenzaldehyde leads to the formation of the compound (IV) and the reaction with a suitably substituted 3-hydroxybenzaldehyde leads to the formation of the compound (IV). Following Schemes 3 to 6, the starting materials for the steps described below are either commercially available or readily accessible to those skilled in the art.

SCHEME 3 Particular aldehydes (IV) can be prepared as shown in scheme 3. A suitable primary alcohol (V) is treated with a base such as sodium hydride, potassium hydride, potassium t-butoxide or lithium diisopropylamide (LDA ), in a polar solvent such as DMF or THF. Preferred conditions include sodium hydride in DMF. The resulting alkoxide is then treated with a substituted 6-chloronicotinonitrile to form an aryl ether of the formula (VII). The reaction can be carried out without heating or with heating to about 60 ° C. Where R5 is H, the compounds of the formula (VII) can be reacted subsequently to install a substituent without hydrogen at that position. The compounds of the formula (VII) are treated with a strong base such as LDA, lithium 2,2,6,6-tetramethylpiperidine (LTMP), or lithium bis (trimethylsilyl) amide (LHMDS), at low temperatures between about -78 ° C and about -50 ° C, in a solvent such as THF, diethyl ether or toluene. Preferred conditions include the use of LDA or LTMP in THF. The resulting litiated species is treated with a suitable electrophile, at temperatures between about -78 ° C and room temperature. Preferred electrophiles are methyl iodide and hexachloroethane. When R5 is chloride, then additional substituents can be introduced at that position using nucleophilic substitution. Suitable nucleophiles include C.sub.3 alkoxides and primary and secondary amines. In a particular embodiment, the preferred nucleophile is methoxide. Once the desired substituents are in place, the nitrile functionality in compounds of the formula (VII) is then reduced with a suitable reducing agent, such as diisobutylaluminum hydride, in a solvent such as toluene or THF, to form aldehydes of the formula (IV) where W is N.

SCHEME 4 Referring to scheme 4, a suitable primary alcohol of the formula (VIII) is reacted with an appropriately substituted 2-chloropyridine of the formula (IX) to generate pyridyl ethers of the formula (X), as shown in scheme 3 The preferred reaction conditions use sodium hydride in DMF. Where R5 is hydrogen, the selected substituents can be introduced at that position by reaction of ethers of the formula (X) with a hindered strong base, followed by a suitable electrophile as described in scheme 3. Preferred electrophiles include iodide of methyl and hexachloroethane. Once the desired substituents are in place, the nitriles of the formula (X) can be reduced to aldehydes of the formula (IV), wherein W is N as shown, through reduction of the nitrile group as described in Scheme 3. Preferred reducing agents include diisobutylaluminum hydride.

SCHEME 5 Referring to scheme 5, dihalogenopyridines of the formula (XI), wherein Hal is either Cl or Br, are reacted with primary alcohols of the formulas (V) or (VIII), using conditions described above, to form pyridoethers of Formula (XII): The resulting 3-halogenopyridines can then be converted to the corresponding 3-formylpyridines of the formula (XIII) by halogen-metal exchange with a suitable alkyl lithium reagent, in a suitable solvent such as THF or diethyl ether, followed by quenching with a formyl equivalent, such as DMF, N-formylpiperidine or ethyl chloroformate. Preferred conditions use n-BuLi or t-BuLi in THF, and a preferred electrophile is DMF. Alternatively, the 3-halogenopyridines of the formula (XII) can be converted to aldehydes of the formula (XIV) in accordance with the directed lithiation and formyl trapping procedures described in schemes 3 and 4. The aldehydes of the formula (XIV) ), where Hal is Br, can be further processed through a three-step sequence to provide aldehydes of the formula (XV). For this purpose, the aldehyde is first protected as a suitable group, such as an acetal. The bromide can then be reacted by halogen-metal exchange using an alkyl lithium reagent and electrophilic entrapment, as described above in the present scheme, to introduce E substituents. Preferred electrophilic reagents include methyl iodide and hexachloroethane, for producing compounds of the formula (XV) wherein E is methyl or chloro, respectively. The aldehydes of formulas (XIII), (XIV), and (XV) can then be processed into compounds of the invention as shown in schemes 1 and 2 above.

SCHEME 6 Referring to scheme 6, the aldehydes of the formula (XIV) can be converted to aminomethyl analogs of the formula (XVI) by reductive amination, using a suitable reducing agent such as NaCNBH3 or Na (OAc3) BH, in a suitable solvent such as 1,2-dichloroethane or methanol. Optional additives may include acetic acid or an Lewis such as ZnCl2. The amines of the formula (XVI) can then be converted to aldehydes of the formula (XVII) by carrying out halogen-metal exchange and extinguishing processes as described above. The aldehydes of the formula (XVII) can be processed into compounds of the In accordance with the scheme 1. Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoiso, these iso can be separated by conventional techniques such as resolution, for example by formation of diastereoc salts, kinetic resolution including variants thereof, such as dynamic resolution, preferential crystallization, biotransformation, enzymatic transformation and preparative chromatography. The compounds can be prepared in racemic form or individual enantio can be prepared either by enantiospecific synthesis or by resolution. The compounds, for example, can be resolved into their component enantiomers by standard techniques such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-) - di-p-toluoyl-D-tartaric acid and / or (+) - di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be separated using a chiral CLAP column. To provide a more concise description, some of the quantitative expressions given here are not quantified with the term "approximately". It is understood that whether the term "approximately" is used explicitly or not, each quantity given here refers to the given real value, and also refers to the approximation to said given value that would reasonably be inferred based on experience in the technique, including approximations due to the experimental and / or measurement conditions for said given value. Expression of the H receptor in immune cells, including some leukocytes and mast cells, establishes as an important target for therapeutic intervention in a range of immunological and inflammatory disorders (such as allergic, chronic or acute inflammation). Specifically, the H 4 receptor ligands are expected to be useful for the treatment or prevention of various disease states in mammals. Therefore, in accordance with the invention, the disclosed compounds, either partial agonists or antagonists of the H 4 receptor, and compositions are useful for the relief of symptoms associated with, the treatment of, and the prevention of, the following conditions and diseases: inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders and immunodeficiency disorders, including the more specific conditions and diseases given above. The described compounds may also be useful as adjuvants in chemotherapy or in the treatment of itching of the skin. Aspects of the invention include (a) a pharmaceutical composition comprising a benzoimidazole compound selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters of the themselves, and a preferred compound as described herein, and a pharmaceutically acceptable carrier; (b) a packaged drug comprising (1) a pharmaceutical composition comprising at least one benzoimidazole compound selected from compounds of formulas (I) and (II), enantiomers, diastereomers, racemates thereof, salts, amides and pharmaceutically acceptable esters thereof, or one or more preferred compounds as described herein, and a pharmaceutically acceptable carrier, and (2) instructions for the administration of said composition for the treatment or prevention of a disease or condition mediated by H4. Modalities of this invention provide methods for the treatment of a condition mediated by H4 in a patient, said methods comprising administering to the patient a pharmaceutically effective amount of a composition comprising at least one benzoimidazole compound selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides, and esters thereof, and other described or preferred compounds. Under these conditions, the action of the H4 receptor is involved. For example, the invention relates to a method for treating a condition mediated by H 4 in a patient, said method comprising administering to the patient a pharmaceutically effective H 4 antagonizing amount of a composition comprising at least one benzoimidazole compound selected from compounds of the formulas (I) and (II), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. As used herein, "treatment" of a grammatically related disorder and terms means eliminating or otherwise alleviating the cause and / or effects thereof.

Terms such as "inhibit", and grammatically related terms, the beginning of a disorder or event, and "prevent" a disorder or condition, in grammatically related terms, mean preventing, slowing or reducing the likelihood of such an onset. The effect of an antagonist can be produced by an inverse agonist. Reverse agonism describes the property of a compound to actively turn off a receptor that displays constitutive activity. The constitutive activity can be identified in cells that have been forced to overexpress the human H4 receptor. The constitutive activity can be measured by examining cAMP levels or by measuring a reporter gene responsive to cAMP levels after a treatment with an AMPc stimulating agent such as forskolin. Cells that overexpress H4 receptors will display lower cAMP levels after treatment with forskolin than cells that do not express them. Cells that behave as H4 agonists will dose-dependently reduce levels of forskolin-stimulated cAMP in cells expressing H4. Compounds that behave as inverse H4 agonists will stimulate cAMP levels in cells that express H4 in a dose-dependent manner. Compounds that behave as H4 antagonists will block either the H4 agonist-induced inhibition of cAMP or increases induced by inverse agonist of H4 in cAMP. Additional embodiments of the invention will include disclosed compounds that are inhibitors of a mammalian histamine H4 receptor function, inhibitors of inflammation or inflammatory responses in vivo or in vitro, modulators of the expression of a mammalian histamine H4 receptor protein, inhibitors of activation of polymorphonuclear leukocytes in vivo or in vitro, or combinations of the above, and methods of treatment, prophylaxis and diagnosis comprising the use of a described compound. The terms "unit dose" and its grammatical equivalent forms are used herein to refer to physically discrete units suitable as unit doses for human and other animal patients, each unit containing a predetermined effective pharmacological amount of the active ingredient calculated to produce the desired pharmacological effect. The specifications for the novel unit dose forms for this invention are determined by, and are directly dependent on, the characteristics of the active ingredient, and the limitations inherent in the technique of combining said active ingredient for therapeutic use in humans and other animals. . The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and combination techniques. Examples of suitable unit dosage forms are tablets, capsules, pills, powder packets, granules, wafers and the like, segregated multiple of any unit dose form, as well as liquid solutions and suspensions. Some liquid forms are aqueous, while other forms of liquid forms are non-aqueous. Oral dosage forms may be elixirs, syrups, capsules, tablets and the like. Examples of solid carriers include those materials generally used in the manufacture of pills or tablets, such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and the like, thickeners such as tragacanth and methylcellulose USP, finely divided SiO2, polyvinyl pyridine, magnesium stearate and the like. Typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as necessary with diluents (eg, sodium and calcium carbonates, sodium and calcium phosphates and lactose), disintegrants (e.g., corn starch and alginic acid), granulating agents, lubricants (e.g. , magnesium stearate, stearic acid and talc), binders (for example, starch and gelatin), thickeners (for example, paraffin, waxes and petrolatum), flavoring agents, coloring agents, preservatives and the like by conventional techniques known to those skilled in the art in the preparation of dosage forms. Coatings may be present and include, for example, glyceryl monostearate and / or glyceryl distearate. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent and soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or oil of olive tree Parenteral dosage forms can be prepared using water or another sterile vehicle. Parenteral solutions can be packaged in containers adapted to be subdivided into individual doses. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, regulated in their pH at an appropriate pH and appropriate isotonicity. Suitable aqueous vehicles include Ringer's solution and sodium chloride sotonic. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, and gum tragacanth, and a wetting agent, such as lecithin. Suitable preservatives for aqueous suspensions include ethyl p-hydroxybenzoate and n-propyl. Parenteral formulations include solutions, dispersions, suspensions, aqueous or non-aqueous emulsions and pharmaceutically acceptable sterile powders for the preparation thereof. Examples of vehicles include water, ethanol, pofioles (propylene glycol, polyethylene glycol), vegetable oils and injectable organic esters such as ethyl oleate. The fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or by maintaining an appropriate particle size. Vehicles for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption accelerators, (g) adsorbers, (h) lubricants, (i) regular pH agents and (j) propellants. The compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersants; antimicrobial agents such as parabens, chlorobutanoi, phenol and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption enhancing agents such as aluminum monostearate and gelatin; and absorption enhancing agents. Physiologically acceptable carriers are well known in the art. Examples of liquid carriers are solutions in which the compounds according to the present invention form solutions, emulsions and dispersions. Compatible antioxidants, such as methylparaben and propylparaben, may be present in solid and liquid compositions, such as sweeteners. The pharmaceutical compositions according to the present invention may include suitable emulsifiers typically used in emulsion compositions. Such emulsifiers are described in standard publications such as Fiedler, 1989, Lexikon der Hilfsstoffe für Pharmazie, Kosmetic und agrenzende Gebiete, Cantor ed., Aulendorf, Germany, and in Handbook of Pharmaceutical Excipients, 1986, American Pharmaceutical Association, Washington, DC, and The Pharmaceutical Society of Great Britain, London, UK, which is incorporated herein by reference. The gelling agents can also be added to compositions according to this invention. Polyacrylic acid derivatives, such as carbomers, are examples of gelling agents, and most particularly, various types of carbopol, which are typically used in amounts of about 0.2% to about 2%. The suspensions may be prepared as a cream, an ointment, including a water-free ointment, a water-in-oil emulsion, an oil-in-water emulsion, an emulsion gel, or a gel. It is envisioned that the compounds of the invention can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, intracystemal, intravaginal, topical or local administration, and inhalation. For oral administration, the compounds of the invention will generally be provided in the form of tablets, capsules or as a solution or suspension. Other methods of administration include controlled release formulations, such as subcutaneous implants or transdermal patches. Effective doses of the compounds of the present invention can be achieved by conventional methods. The specific dose level required for any particular patient will depend on a number of factors, including the severity of the condition, type of symptoms needing treatment, the route of administration, the weight, age and general condition of the patient, and the administration of other medications In general, it is envisaged that the daily dose (either administered as a single dose or as a divided dose) will be in the range of from about 0.01 mg to about 1000 mg per day, very generally from about 1 mg to about 500 mg per day , and very generally from about 10 mg to about 200 mg per day. Expressed as dose per unit body weight, a typical dose will be expected to be between about 0.0001 mg / kg and about 15 mg / kg, especially between about 0.01 mg / kg and about 7 mg / kg, and very specifically between about 0.15 mg / kg. kg and 2.5 mg / kg. The predicted oral dose ranges include from about 0.01 to 500 mg / kg, daily, most preferably from about 0.05 to about 100 mg / kg, taken in 1-4 separate doses. Some compounds of the invention can be applied as oral doses in the range of about 0.05 to about 50 mg / kg daily, while others can be dosed at 0.05 to about 20 mg / kg daily. The infusion doses may vary from about 1.0 to about 1.0 x 104 μg / (kg.min) of inhibitor, mixed with a pharmaceutical carrier for a period ranging from a few minutes to several days. For topical administration, the compounds of the present invention can be mixed with a pharmaceutical carrier at a concentration of about 0.1 to about 10% drug to the vehicle. Capsules, tablets or other formulations (such as liquids and film-coated tablets) can be between 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60 mg and 100 mg and are They can be administered according to the methods described. It is contemplated that daily doses are, for example, between 10 mg and 5000 mg for an adult human of normal weight.

EXAMPLES General experimental procedures The NMR spectra were obtained either in a Bruker spectrometer model DPX400 (400 MHz) or DPX500 (500 MHz). The format of the 1 H NMR data given below is: chemical shift in ppm field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration). The mass spectra were obtained in a Hewlett Packard (Agilent) series 1100 MSD using electroaspersion ionization (ESI) either in positive or negative mode as indicated. The "calculated mass" for a molecular formula is the monoisotopic mass of the compound.

Purification Method 1: Reversed phase CLAP The retention times of CLAP are reported in minutes, using the methods and conditions reported below. Instrument: Aglient HP-1100 Solvent: Acetonitrile (0.05% TFA) / H2O (TFA al 0. 05%) Flow rate: 0.75 ml / min Gradient: 1 min to 1% H20; linear ramp from 7 minutes to 99% CH3CN; Column: Zorbax Eclipse XDB-C8 (5 um, 4. 6x150 mm) Temperature: 35 ° C Wavelength: Double detection at 220 and 254 nM Purification Method 2: Normal Phase Chromatography 2-Arubenzimidazoles were purified by chromatography on silica gel eluting with dichloromethane, then 10% methanol in dichloromethane and subsequently 10% (2.0 M ammonia in methanol) in dichloromethane. The reaction mixtures were loaded onto the silica gel without treatment.

EXAMPLE 1 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4,5-dimethyl-1H-benzoimidazole General procedure 1 A. 2-Chloro-4- (3-chloro-propoxy) -benzaldehyde. 1-Bromo-3-chloropropane (2.55 g, 16.2 mmol, 1.0 equiv.) Was added to a solution of 2-chloro-4-hydroxybenzaldehyde (2.54 g, 16.2 mmol, 1.0 equiv.) And K2C03 (4.48 g, 32.4 mmol, 2.0 equiv.) In acetonitrile (41 ml). The mixture was heated at 65 ° C for 18 hr, then cooled to room temperature (room temperature) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to give 3.19 g of a colorless oil (66%). 1 H NMR (400 MHz, CD 3 OD): 10.3 (s, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.10 (d, J = 4.0 Hz, 1 H), 7.03 (dd, J = 8.0, 4.0 Hz, 1 H), 4.23 (t, J = 8.0 Hz, 2H), 3.76 (t, J = 8. 0 Hz, 2H), 2.31-2.22 (m, 2H).

General procedure 2 B. 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxp-benzaldehyde. N-Methylpiperazine (2.16 g, 21.5 mmol, 2.0 equiv.), 2-chloro-4- (3-chloro-propoxy) -benzaldehyde (3.19 g, 10.8 mmol, 1.0 equiv.), K2C03 (4.46 g, 32.3 mmol, 3.0 equiv.), And Kl (1.02 g, 5.38 mmol, 0.5 equiv.) Were stirred in n-butanol (22 ml) at 90 ° C for 18 hr. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated to give the crude product, which was purified by method 2 to give 2.04 g (63%) of orange oil. 1 H NMR (400 MHz, CD 3 OD): 10.3 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 7.00 (dd, J = 8.0, 2.0 Hz, 1 H), 4.15 (t, J = 8.0 Hz, 2H), 3.00-2.30 (br s, 10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).

General procedure 3 C. 2-. { 2-Chloro-4-f3- (4-methyl-piperazin-1-yl) -propoxp-phenol} -4,5-dimethyl-1 H-benzoimidazole. 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -benzaldehyde (91.5 mg, 0.31 mmol, 1.0 equiv.) And 3,4-dimethyl-benzene-1,2-diamine (42 mg, 0.31 mmol, 1.0 equiv.) Were stirred with Na2S205 (76 mg, 0.40 mmol, 1.3 equiv.) In DMF (0.25 M) at 90 ° C for 12 hr. The reaction mixture was loaded directly onto silica gel and purified according to method 2, which gave 98 mg (76%) of the title compound. MS (electroaspersion): mass calculated for C23H29CIN4O, 412.20; m / z found, 413.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.68 (br s, 1 H), 7.33 (br s, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 7.07 (d, J = 8.7, 2.5 Hz, 1H), 7.03 (dd, J = 8.7, 2.5 Hz, 1H), 4.13 (t, J = 6.1 Hz, 2H), 2.60-2.39 (m, 13H), 2.39 (s, 3H), 2.30 (s, 3H) ), 2.05-1.95 (m, 2H).

EXAMPLE 2 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole A. 3- (1-Methyl-piperidin-4-yl) -propan-1-ol. To a refluxing solution of 1 N lithium aluminum hydride in THF (40 mmol) was added dropwise a solution of N-BOC-4-piperidinpropionic acid (3.0 g, 11.6 mmol) in THF (30 mL). The reaction mixture was heated for 3 hr and then cooled to room temperature. After further cooling to 0 ° C, water (1.5 ml) was added slowly, and the reaction mixture was allowed to warm to room temperature for 15 min. The mixture was again cooled to 0 ° C, and 10% NaOH (1.5 ml) was added slowly. After warming to room temperature for 15 min, the mixture was again cooled to 0 ° C and more water (4.5 ml) was added. The resulting mixture was allowed to warm to room temperature for 18 hr, and then filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by method 2 to give 1.9 g (100%) of 3- (1-methyl-piperidin-4-ii) -propan-1-ol as a yellow oil. MS (electroaspersion): mass calculated for C9H19NO, 157.15; m / z found, 158.1 [M + H] +. 1 H NMR (400 MHz, CD3OD): 3.45-3.41 (m, 2H), 2.77-2.74 (m, 2H), 1.89-1.85 (m, 2H), 1.64-1.61 (m, 2H), 1.47-1.43 (m, 2H), 1.21-1.12 (m, 5H). B. 2-Chloro-4-y3- (1-methyl-piperidin-4-yl) -propoxy-1-benzaldehyde. To an ice-cooled solution of 2-chloro-4-hydroxybenzaldehyde (507 mg, 3.2 mmol, 1.0 equiv.), Triphenylphosphine (1.02 g, 3.9 mmol, 1.2 equiv.), And 3- (1-methyl-piperidin-4) -yl) -propan-1-ol (508 mg, 3.9 mmol, 1.2 equiv.) in THF (15 ml) was added diethyl azodicarboxylate (DEAD, 0.6 ml, 3.2 mmol, 1.0 equiv.). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hr. The mixture was diluted with water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated. Purification by method 2 gave 768 mg (80%) of the desired aldehyde. MS (electroaspersion): mass calculated for C 16 H 23 NO 2, 261.17; m / z found, 262.2 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 9.85 (s, 1 H), 7.80 (d, J = 8.6 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 4.01 (t, J = 6.4 Hz, 2H), 2.84-2.82 (m, 2H), 2.25 (s, 3H), 1-92-1.78 (m, 4H), 1.71-1.69 (m, 2H), 1.41-1.37 (m, 2H), 1.29- 1.26 (m, 3H). C. 2- (2-Chloro-4-r3- (1-methyl-piperidin-4-y-propoxy-1-phenyl) -4-methyl-1H-benzoimidazole 2-Chloro-4 - [3- (1-methyl-p-peridin-4-yl) -propoxy] -benzaldehyde and 3-methyl-benzene-1,2-diamine was stirred with Na 2 SO 5 in DMF at 90 ° C for 12 hr. Purification of the reaction mixture by method 2 gave 129 mg (73%) of the title compound. MS (electroaspersion): mass calculated for C23H28CIN3O, 397.19; m / z found, 398.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.69 (d, J = 8.5 Hz, 1H), 7.46-7.35 (m, 1 H), 7.17-7.13 (m, 2H), 7.06-7.01 (m, 2H), 4.06 (t, J = 6.4 Hz, 2H), 2.95-2.85 (m, 2H), 2.59 (s, 3H), 2.27 (s, 3H), 2.10-1.95 (m, 2H), 1.86-1.76 (m, 4H) ), 1.50-1.49 (m, 2H), 1.32-1.25 (m, 3H).

EXAMPLE 3 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-ii) -propoxy] -phenyl} -5-trifluoromethoxy-1H-benzoimidazole This compound was prepared by the method described in general procedure 3 using 2-chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -benzaldehyde (200 mg, 0.68 mmol, 1.0 equiv.), 4-trifluoromethoxy-benzene-1,2-diamine (119 mg, 0.62 mmol, 0.92 equiv.) and Na2S205 (167 mg, 0.88 mmol, 1.3 equiv.). Purification by method 2 gave 72 mg (23%) of the title compound. MS (electroaspersion): mass calculated for C22H24CIF3N4O2, 468.15; m / z found, 469.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.82 (d, J = 8.7 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.55 (s, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.1 (dd, J = 8.6, 2.2 Hz, 1H), 4.17 (t, J = 5.7 Hz, 2H), 2.88-2.38 (m , 10H), 2.32 (s, 3H), 2.10-1.95 (m, 2H).

EXAMPLE 4 -Ier-Butyl-2-. { 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -pheni} -1 H- benzoimidazole This compound was prepared by the method described in example 1, using 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -benzaldehyde ( 62 mg, 0.20 mmol, 1.0 equiv.), 4-fer-butyl-benzene-1,2-diamine (33 mg, 0.20 mmol, 1.0 equiv.), And Na2S205 (50 mg, 0.26 mmol, 1.3 equiv.) In the general procedure 3. Purification by method 2 gave 31 mg (34%) of the title compound. EM (electroaspersion): mass calculated for C26H35CIN4O, 454.25; m / z found, 455.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.12 (d, J = 2.2 Hz, 1 H), 7.98 (dd, J = 8.6, 2.3 Hz, 1 H), 7.6 (s, 1 H), 7.52 (d, J = 8. 5 Hz, 1 H), 7.37 (dd, J = 8. 6.1.8 Hz, 1H), 7.22 (d, J = 8.7Hz, 1H), 4.19 (t, J = 6.0 Hz, 2H), 2.84 -2.74 (m, 10H), 2.40 (s, 3H), 2.08-1.97 (m, 2H), 1.90-1.83 (m, 2H), 1.41 (s, 9H).

EXAMPLE 5 -fer-Butyl-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole This compound was prepared by the method described in the example 2, using 3-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzaldehyde (98.6 mg, 0.36 mmol, 1.0 equiv.), 4-fer-butyl-benzene-1, 2-diamine (59 mg, 0.36 mmol, 1.0 equiv.), And Na S2? S (89 mg, 0.47 mmol, 1.3 equiv.) In step C. Purification by method 2 gave 116 mg (77%) of the title compound. MS (electroaspersion): mass calculated for C27H37N3O, 419.29; m / z found, 420.2 [M + Hf. 1 H NMR (400 MHz, CD3OD): 7.90-7.82 (m, 2H), 7.60-7.50 (m, 1H), 7.52-7.40 (m, 1H), 7.33 (dd, J = 8. 5,1.8 Hz, 1 H), 7.02- (d, J = 9.1Hz, 1H), 4.07 (t, J = 6.2 Hz , 2H), 2.92-2.85 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.80 (m, 2H), 1.80-1.70 (m , 2H), 1.55-1.45 (m, 2H), 1.49 (s, 9H), 1.49-1.26 (m, 3H).

EXAMPLE 6 4,5-Dimethyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole This compound was prepared by the method described in Example 1, using 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -benzaldehyde (180 mg, 0.65 mmoies, 1.0 equiv.), 3,4-dimethyl-benzene-1,2-diamine (89 mg, 0.65 mmol, 1.0 equiv.), And Na2S2? 5 (161 mg, 0.85 mmol, 1.3 equiv.) In general procedure 3 Purification by method 2 gave 192 mg (75%) of the title compound. MS (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.5 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.95-7.85 (m, 2H), 7.35-7.23 (m, 1 H), 7.08-7.00 (m, 2H), 4.12 (t, J = 6.0 Hz, 2H), 2.64 -2.37 (m, 16H), 2.29 (s, 6H), 2.10-2.00 (m, 2H).

EXAMPLE 7 -fer-Butyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1H-benzoimidazol. This compound was prepared by the method described in Example 1, using 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -benzaldehyde (53 mg, 0.19 mmol, 1.0 equiv.), 4-fer -butylbenzene-1, 2-diamine (32 mg, 0.19 mmol, 1.0 equiv.), and Na2S2? s (48 mg, 0.25 mmol, 1.3 equiv.) in general procedure 3. Purification by method 2 gave 75 mg (92%) of the title compound. MS (electroaspersion): mass calculated for C 26 H 36 N 4 O, 420.29; m / z found, 421.2 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.68-7.56 (m, 3 H), 7.54 (br d, J = 8.2 Hz, 1 H), 7.44-7.36 (m, 2 H), 7.02 (dd, J = 8.2, 2.2 Hz, 1 H), 4.07 (t, J = 6.1 Hz, 2H), 3.00-2.26 (m, 10H), 2.26 (s, 3H), 1.85-1.75 (m, 2H), 1.75-1.65 (m, 2H ), 1.40 (s, 9H).

EXAMPLE 8 -Ier-Butyl-2-. { 3- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole A.3- (4-Chloro-butoxy) -benzaldehyde. This intermediate was prepared by the method described in general procedure 1 using 3-hydroxybenzaldehyde (2.0 g, 16.4 mmol, 1.0 equiv.), 1-bromo-4-chlorobutane. (1.62 ml, 16.4 mmol, 1.0 equiv.), And K2C03 (4.53 g, 33 mmol, 1.0 equiv.).

Purification gave 2.57 g (79%) of the desired product. 1 H NMR (400 MHz, CDCl 3): 9.98 (s, 1 H), 7.47-7.43 (m, 2 H), 7.40-7.37 (m, 1 H), 7.27-7.25 (m, 1 H), 4.09-4.03 ( m, 2H), 3.66- 3.58 (m, 2H), 2.03-1.93 (m, 4H). B, 5-tert-Butyl-2-f3- (4-chloro-butoxyphenip-1H-benzoimidazole) This intermediate was prepared by the method described in general procedure 3 using 3- (4-chloro-butoxy) -benzaldehyde ( 500 mg, 2.52 mmol, 1.0 equiv.), 4-tert-butyl-benzene-1,2-diamine (414 mg, 2.52 mmol, 1.0 equiv.), And Na2S205 (622 mg, 3.3 mmol, 1.3 equiv.). The reaction mixture was loaded onto a column of silica gel and purified by flash chromatography (25% ethyl acetate in hexanes) to give 348 mg (40%) of the desired product. 1 H NMR (400 MHz, CDCl 3): 7.72-7.48 (m, 4H), 7.47-7.35 (m, 2H), 7.08-7.03 (m, 1 H), 4.17-4.10 (m, 2H), 3.70-3.64 (m, 2H), 2.03-1.96 ( m, 4H), 1.41 (s, 9H) C. 5-fer-Butyl-2- {3-r4- (4-methyl-f-1, 41-diazepane-1-yl-Vbutoxp-fenift-1 H-benzoimidazole. This compound was prepared by the method described in general procedure 2 using 5-tert-butyl-2- [3- (4-chloro-butoxy) -phenyl] -1H-benzoimidazole (51.2 mg, 0.15 mmol, 1.0 equiv.) , N-methyl-homo-piperazine (19 μl, 0.15 mmo les, 1.0 equiv.), K2C03 (40 mg, 0.30 mmol, 2.0 equiv.), and Kl (12 mg, 0.08 mmol, 0.5 equiv.). Purification by method 2 gave 19 mg (23%) of the title compound. EM (electroaspersion): mass calculated for C27H38N4O, 434.30; m / z found, 435.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.66-7.62 (m, 3 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.45-7.35 (m, 1 H), 7.37 (dd, J = 8.6, 1.8 Hz , 1 H), 7.06-7.02 (m, 1 H), 4.11 (t, J = 6.2 Hz, 2H), 2.78-2.75 (m, 4H), 2.69-2.65 (m, 4H), 2.60-2.55 (m , 2H), 2.32 (s, 3H), 1.85-1.79 (m, 4H), 1.75-1.68 (m, 2H), 1.40 (s, 9H).

EXAMPLE 9 (1- { 3- [4- (5-tert-Butyl-1 H-benzoimidazol-2-yl) -2-chloro-phenoxy] -propii.} -pyrrolidin-3-yl ) - dimethylamine. This compound was prepared by the method described in Example 1, using 5-tert-butyl-2- [3- (4-chloro-butoxy) -phenyl] -1H-benzoimidazole (206 mg, 0.55 mmol, 1.0 equiv. ), dimethyl-pyrrolidin-3-yl-amine (125 mg, 1.09 mmol, 2.0 equiv.), K2C03 (227 mg, 1.64 mmol, 3.0 equiv.), and Kl (46 mg, 0.27 mmol, 0.5 equiv.) in the general procedure 3. Purification by method 2 gave 137 mg (55%) of the title compound. MS (electroaspersion): mass calculated for C26H35CIN4O, 454.25; m / z found, 455.5 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.11 (d, J = 2.2 Hz, 1 H), 7.97 (dd, J = 8.6, 2.2 Hz, 1 H), 7.58 (br s, 1 H), 7.65-7.45 (m, 1 H), 7.36 (dd, J - 8.6, 1.7 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 1 H), 4.21 (t, J = 6.0 Hz, 2H), 3.04-2.99 (, 1 H), 2.91-2.65 (m, 4H), 2.56-2.49 (m, 1H), 2.36-2.29 ( m, 1H), 2.24 (s, 6H), 2.10-1.99 (m, 3H), 1.79-1.70 (m, 1 H), 1.40 (s, 9H).

EXAMPLE 10 -Chloro-2-. { 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -6-methyl-1 H-benzoimidazole This compound was prepared by the method described in Example 1, using 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy ] -benzaldehyde (61 mg, 0.20 mmol, 1.0 equiv.), 4-chloro-5-methyl-benzene-1,2-diamine (31 mg, 0.20 mmol, 1.0 equiv.), and Na2S205 (48 mg, 0.25 mmol) , 1.3 equiv.) In the general procedure 3. Purification by method 2 gave 7.1 mg (8%) of the title compound. MS (electroaspersion): mass calculated for C23H28CI2N4O, 446.16; m / z found, 447.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.96 (d, J = 2.2 Hz, 1 H), 7.83 (dd, J = 8.6, 2.2 Hz, 1 H), 7.45 (s, 1 H), 7.34 (s, 1 H), 7.10 (d, J = 8.7 Hz, 1 H), 4.08 (t, J = 6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36 (s, 3H), 2.30 (s, 3H) , 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).

EXAMPLE 11 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-ii) -propoxy] -phenyl} -4-methyl-1H-benzoimidazole This compound was prepared by the method described in example 1, using 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -benzaldehyde (94 mg , 0.34 mmol, 1.0 equiv.), 3-methyl-benzene-1,2-diamine (42 mg, 0.34 mmol, 1.0 equiv.), And Na2S2? 5 (84 mg, 0.44 mmol, 1.3 equiv.) In the procedure General 3. Purification by method 2 gave 130 mg (100%) of the title compound.

MS (electroaspersion): mass calculated for C22H27FN4O, 382.22; m / z found, 383.2 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.86-7.78 (m, 2 H), 7.40-7.37 (m, 1 H), 7.12-6.97 (m, 3 H), 3.99 (t, J = 6.1 Hz, 2 H), 3.00- 2.30 (m, 13H), 2.25 (s, 3H), 1.94-1.90 (m, 2H).

EXAMPLE 12 -Methyl-2-. { 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -naphthalene-1-yl} -1 H-benzoimidazole This compound was prepared by the method described in the example 1, using 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -naphthalene-1-carbaldehyde (63 mg, 0.20 mmol, 1.0 equiv.), 4-methyl-benzene-1, 2- diamine (24 mg, 0.20 mmol, 1. 0 equiv.), And Na2S205 (49 mg, 0.26 mmol, 1.3 equiv.) In the general procedure 3. The desired product was isolated from the reaction mixture using method 1 and subsequently purified again by method 2 to give 54. 6 mg (66%) of the title compound. MS (electroaspersion): mass calculated for C26H30N4O, 414.24; m / z found, 415.62 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.48 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8. 4 Hz, 1 H), 8.0 (d, J = 8.2 Hz, 1 H), 7.78-7.65 (m, 4H), 7.50 (d, J = 8.4 Hz, 1 H), 7.21 (d, J = 8.2 Hz , 1 H), 4.43 (t, J = 6.0 Hz, 2H), 3.40 (brs, 4H), 3.30-3.00 (m, 6H), 2.88 (s, 3H), 2.59 (s, 3H), 2.36- 2.30 (m, 2H).

EXAMPLE 13 4- [3- (5-tert-Butyl-1H-benzoimidazol-2-jl) -phenoxy-1 - (4-methyl-piperazin-1-yl) -butan-1-one A. 3-f4- ( 4-Methyl-piperazin-1-yl) -4-oxo-butoxy] -benzaldehyde. To a solution of 4- (3-formyl-phenoxy) -butyric acid (981 mg, 4.72 mmol, 1.0 equiv.) And N-methylpiperazine (576 mg, 5.19 mmol, 1.1 equiv.) In dichloromethane at 0 ° C was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCl, 1.18 g, 6.14 mmol, 1.3 equiv.) And 1-hydroxybenzotriazole hydrate (HOBT); 701 mg, 5.19 mmol, 1.1 equiv.). The reaction mixture, which was allowed to warm to room temperature, was stirred for 2.0 hr and then poured into water. This mixture was extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 5% MeOH in dichloromethane) to give 847 mg (62%) of the desired product. 1 H NMR (400 MHz, CD 3 OD): 9.72 (s, 1 H), 7.29-7.23 (m, 2 H), 7.22-7: 19 (m, 1 H), 7.05-6.98 (m, 1 H), 3.87 ( t, J = 6.1 Hz, 2H), 3.43-3.31 (m, 4H), 2.39 (t, J = 7.2 Hz, 2H), 2.27-2.17 (m, 4H), 2.08 (s, 3H), 1.92-1.80 (m, 2H). B. 4- [3- (5-tert-Butyl-1H-benzoimidazole-2-y-phenoxy-1- (4-methyl-piperazin-1-yl) -butan-1-one) This compound was prepared by the method described in general procedure 3 using 3- [4- (4-methyl-piperazin-1-yl) -4-oxo-butoxy-benzaldehyde (81.2 mg, 0.28 mmol, 1.0 equiv.), 4-tert. butyI-benzene-1, 2-diamine (46 mg, 0.28 mmol, 1.0 equiv.), and Na2S205 (69 mg, 0.36 mmol, 1.3 equiv.) Purification by method 2 gave 77 mg (64%) of the compound of the title MS (electroaspersion): mass calculated for C26H34N4O2, 434.27, m / z found, 435.0 [M + Hf. 1 H NMR (400 MHz, CD3OD): 7.69-7.62 (m, 3H), 7.54 (d, J = 8.6 Hz, 1 H), 7.45-7.37 (m, 2H), 7.06 (dd, J = 8.2, 2.2 Hz, 1 H), 4.13 (t, J = 6.1 Hz, 2H), 3.70-3.50 (m, 4H ), 2.62 (t, J = 7.3 Hz, 2H), 2.49-2.40 (m, 4H), 2.32 (s, 3H), 2.16-2.09 (m, 2H), 1.41 (s, 9H).

EXAMPLE 14 -Chloro-2- [3-chloro-4- (3-piperazin-1-yl-propoxy) -phenyl] -6-fluoro-1 H-benzoimidazole A. 4- Tert-butyl ester. { 3-r2-Chloro-4- (5-chloro-6-fluoro-1 H -benzoimidazol-2-yl) -phenoxy-propyl-piperazine-1-carboxylic acid. This compound was prepared by the method described in Example 1, using 4- [3- (2-chloro-4-formyl-phenoxy) -propy] -piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.6 mmoles, 1.0 equiv.), 4-chloro-5-fluoro-benzene-1,2-diamine (421 mg, 2.6 mmol, 1.0 equiv.), and Na2S20s (648 mg, 3.4 mmol, 1.3 equiv.) in the procedure General 3. Purification by method 2 gave 256 mg (15%) of the title compound. EM (electroaspersion): mass calculated for C25H2gC? 2FN4? 3, 522. 16; m / z found, 545.3 [M + Na] +. B. 5-Chloro-2-f3-chloro-4- (3-piperazin-1-yl-propoxy) -fenip-6-fluoro-1 H-benzoimidazole. To a suspension of ter-butyl ester of 4- acid. { 3- [2-chloro-4- (5-chloro-6-fluoro-1 H -benzoimidazol-2-yl) -phenoxy] -propyl} Piperazine-1-carboxylic acid (52.7 mg, 0.10 mmol) in dichloromethane (1.0 ml) at room temperature was added TFA (1.0 ml), and the reaction mixture was stirred for 50 min. The mixture was concentrated under reduced pressure, and the solid residue was washed four times with dichloromethane. The title compound was obtained in quantitative yield as the TFA salt. EM (electroaspersion): mass calculated for C20H21CI2FN4O, 422. eleven; m / z found, 423.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.17 (d, J = 2.3 Hz, 1 H), 8.03 (dd, J = 8.7, 2.3 Hz, 1 H), 7.81 (d, J = 6.4 Hz, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 4.33 (t, J = 5.8 Hz, 2H), 3.50-3.47 (m, 4H), 3.36 (br s, 4H), 3.25 (t, J = 7.4 Hz, 2H), 2.33-2.26 (m, 2H).

EXAMPLE 15 -tert-Butyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole This compound was prepared by the method described in example 1, using 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -benzaldehyde (516 mg, 1.87 mmol, 1.0 equiv.), 4-tert-butyl-benzene-1,2-diamine (307 mg, 1.87 mmol, 1.0 equiv.), And Na2S205 (461 mg, 2.43 mmol, 1.3 equiv.) In the general procedure 3. The purification by method 2 gave 633 mg (81%) of the title compound. MS (electroaspersion): mass calculated for C 26 H 36 N 4 O, 420.29; m / z found, 421.5 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.90-7.85 (m, 2 H), 7.65-7.40 (m, 2 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.1 Hz, 1 H), 4.14-4.11 (m, 2H), 2.90-2.28 (m, 16H), 2.06-2.03 (m, 2H), 1.39 (s, 9H).

EXAMPLE 16 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} 4,6-dimethyl-1H-benzoimidazole This compound was prepared by the method described in the example 2, using 2-chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzaldehyde (106 mg, 0.36 mmol, 1.0 equiv.), 3,5-dimethyl-benzene-1, 2-diamine (49 mg, 0.36 mmol, 1.0 equiv.), And Na2S205 (88 mg, 0.47 mmol, 1.3 equiv.) In step C. Purification by method 2 gave 128 mg (87%) of the title compound. MS (electroaspersion): mass calculated for C24H30CIN3O, 411.21; m / z found, 412.4 [M + Hf. H NMR (400 MHz, CD3OD): 7.68 (d, J = 8.5 Hz, 1 H), 7.21 (brs, 1 H), 7.12 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.7, 2.5 Hz, 1H), 6.90 (s, 1 H), 4.05 (t, J = 6.3 Hz, 2H), 2.92-2.88 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.09-2.03 (m, 2H), 1.85-1.76 (m, 4H), 1.47- 1.11 (m, 5H). The following compounds in Examples 17-56 were prepared using general procedures 1, 2 and 3 as illustrated by way of example above.

EXAMPLE 17 2-. { 2-Chloro-4- [2-methyl-3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN4 ?, 412.20; m / z found, 413.2 [M + Hf. 1 H NMR (400 MHz, CD3OD): 7.75-7.65 (m, 1 H), 7.50-7.35 (m, 1 H), 7.20-7.13 (m, 2H), 7.15-7.02 (m, 2H), 4.06 (dd, J = 9.2, 4.5 Hz, 1 H), 3.94 (dd, J = 9.2, 6.0 Hz, 1 H ), 2.80-2.35 (m, 13H), 2.35-2.20 (m, 4H), 2.28 (d, J = 4.5 Hz, 3H).

EXAMPLE 18 -Chloro-2-. { 3-chloro-4- [3- (4-methyl-piperazin-1-ii) -propoxy] -phenyl} -6-metii-1H-benzoimidazole MS (electroaspersion): mass calculated for C22H26Cl2N40, 432.15; m / z found, 432.8 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.19 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 8.6, 2.2 Hz, 1H), 7.66 (br s, 1 H), 7.55 (br s, 1H ), 7.32 (d, J = 8.7 Hz, 1 H), 4.30 (t, J = 6.0 Hz, 2H), 3.00-2.43 (m, 13H), 2.42 (s, 3H), 2.18-2.14 (m, 2H) ).

EXAMPLE 19 6-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H26Cl2N O, 432.15; m / z found, 433.1 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.70 (br s, 1 H), 7.42 (br s, 1 H), 7.17 (d, J = 2.4 Hz, 1 H), 7.08 (br s, 1 H), 7.05 (dd) , J = 8.7.2.5 Hz, 1 H), 4.13 (t, J = 6.14 Hz, 2H), 3.00-2.40 (m, 13H), 2.30 (s, 3H), 2.03-1.98 (m, 2H).

EXAMPLE 20 -tert-Butyl-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazoi EM (electroaspersion): mass calculated for C25H33CIN4O, 440.23; m / z found, 441.0 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.31 (d, J = 2.2 Hz, 1 H), 8.17 (dd, J = 8.6, 2.2 Hz, 1 H), 7.78 (br s, 1 H), 7.69 (brs, 1H), 7.55 (dd, J = 8.6, 1.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1 H), 4.40 (t, J = 6.0 Hz, 2H), 3.00-2.55 (m, 10H) , 2.51 (s, 3H), 2.35-2.22 (m, 2H), 1.59 (s, 9H).

EXAMPLE 21 -Chloro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C21H24CIFN4O, 402.16; m / z found, 403.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.86-7.83 (m, 2 H), 7.64 (d, J = 1.9 Hz, 1 H), 7.60 (d, J = 8.7 Hz, 1 H), 7.39 (dd, J = 8.7, 1.9 Hz, 1H), 7.33-7.29 (m, 1 H), 4.21 (t, J = 5.9 Hz, 2H), 3.20-2.77 (m, 10H), 2.76 (s, 3H), 2.10-2.03 ( m, 2H).

EXAMPLE 22 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4,6-dimeiii-1 H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 31 CIN 4 O, 426.22; m / z found, 427.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.58 (d, J = 8.6 Hz, 1 H), 7.11 (s, 1 H), 7.03 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J = 8.7, 2.5 Hz, 1H), 6.80 (s, 1 H), 3.99 (t, J = 6.1 Hz, 2H), 2.75-2.58 (m, 10H), 2.45 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H), 1.89-1: 85 (m, 2H), 1.78-1.74 (m, 2H).

EXAMPLE 23 -Chloro-6-methyl-2- [3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN40, 412.20; m / z found, 413.1 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.60-7.56 (m, 3 H), 7.44-7.37 (m, 2 H), 7.03-7.00 (m, 1 H), 4.05 (t, J = 6.1 Hz, 2 H), 3.00 -2.30 (m, 13H), 2.27 (s, 3H), 1.82-1.73 (m, 2H), 1.72-1.67 (m, 2H). 13 C NMR (TFA salt, 100 MHz, CD3OD): 161.0, 154.0, 138.5, 131.9, 131.7, 131.3, 130.2, 120.0, 118.2, 116.7, 116.2, 113.4, 68.7, 58.0, 54.2, 51.7, 44.2, 27.8, 23.5 , 20.8.

EXEMPLC) 24 -Chloro-6-fluoro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C21H23CIF2N4O, 420.15; m / z found, 421.2 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.80-7.75 (m, 2H), 7.66 (d, J = 6.4 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.27 (t, J = 9.3 Hz, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.25 (brs, 4H), 3.02 (br s, 4H), 2.90 (t, J = 7.8 Hz, 2H), 2.81 (s, 3H), 2.12-2.05 (m, 2H).

EXAMPLE 25 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-metii-1 H-benzoimidazole EM (electroaspersion): mass calculated for C22H27FN4O, 382.22; m / z found, 383.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.85-7.80 (m, 2 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.49 (s, 1 H), 7.38-7.34 (m, 2 H), 4.22 ( t, J = 5.9 Hz, 2H), 3.24 (br s, 4H), 2.95 (br s, 4H), 2.84 (t, J = 7.2 Hz, 2H), 2.77 (s, 3H), 2.46 (s, 3H) ), 2.12-2.05 (m, 2H).

EXAMPLE 26 ,6-Difluoro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C21H23F3N4O, 404.18; m / z found, 405.2 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.79-7.73 (m, 2H), 7.50-7.45 (m, 2H), 7.28-7.22 (m, 1H), 4.18 (t, J = 5.9 Hz, 2H), 3.04-2.83 (m, 1 OH), 2.76 (s, 3H), 2.10-2.03 (m, 2H).

EXAMPLE 27 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C2H25FN4O, 368.20; m / z found, 369.3 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.88-7.81 (m, 2 H), 7.71-7.66 (m, 2 H), 7.52-7.48 (m, 2 H), 7.37 (t, J = 8.8 Hz, 1 H), 4.22 ( t, J = 6.0 Hz, 2H), 3.04-2.76 (m, 13H), 2.10-2.03 (m, 2H).

EXAMPLE 28 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4,5-dimethyl-1 H- benzoimidazole EM (electroaspersion): mass calculated for C24H31CIN4O, 426. 22; m / z found, 427.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.75-7.65 (m, 1 H), 7.40-7.25 (m, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 7.04 (dd, J = 8.6.2.5 Hz, 1 H), 4.13 (t, J = 6.1 Hz, 1 H), 2.85-2.70 (m, 10H), 2.51 (brs, 3H), 2.42 ( s, 3H), 2.40 (s, 3H), 2.02-1.96 (m, 2H), 1.88-1.86 (m, 2H). 13C NMR (100 MHz, CD3OD): 13.7, 19.4, 24.2, 26.9, 45.0, 50.9, 54.7, 55.4, 55.9, 56.6, 67.4, 112.2, 115.2, 117.7, 118.9, 123.7, 128.8, 133.6, 134.5, 134.7, 135.2 , 135.5, 148.9, 163.5.

EXAMPLE 29 , 6-Dimethyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 5.96. MS (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.57-7.50 (m, 3 H), 7.48 (s, 2 H), 7. 23-7.20 (m, 1H), 4.08 (t, J = 5.8 Hz, 2H), 3.16 (br s, 4H), 3.01 (br s, 4H), 2.82-2.79 (m, 2H), 2.71 (s, 3H), 2.38 (s, 6H), 1.85-1.74 (m, 4H).

EXAMPLE 30 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -4,6-dimetiI-1 H-benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN4O, 412.20; m / z found, 413.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.68 (d, J = 8.5 Hz, 1 H), 7.21 (br s, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 7.03 (dd, J = 8.7.2.5 Hz, 1 H), 6.90 (s, 1 H), 4.13 (t, J = 6.2 Hz, 2H), 2.70-2.40 (m, 16H), 2.96 (s, 3H), 2.06-1.98 (m , 2H).

EXAMPLE 31 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4-metii-1 H- benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN4O, 412.20; m / z found, 413.4 [M + H. 1 H NMR (400 MHz, CD 3 OD): 7.72-7.69 (m, 1H), 7.50-7.35 (m, 1 H), 7.18-7.13 (m, 2H), 7.06-7.03 (m, 2H), 4.14 (t, J = 6.1 Hz, 2H), 2.85-2.70 (m, 10H), 2.59 (s, 3H), 2.40 (s, 3H), 2.02-1.96 (m, 2H), 1.89-1.85 (m, 2H).

EXAMPLE 32 -tert-Butyl-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzolmidazole EM (electroaspersion): mass calculated for C25H33CIN4O, 440.23; m / z found, 441.5 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.76 (d, J = 8.7 Hz, 1 H), 7.62-7.53 (m, 2H), 7.38 (dd, J = 8.6, 2.0 Hz, 1 H), 7.15 (d, J = 2.5 Hz, 1H), 7.04 (dd, J = 8.7, 2.5 Hz, 1 H), 4.13 ( t, J = 6.1 Hz, 2H), 2.80-2.20 (m, 13H), 2.06-1.96 (m, 2H), 1.40 (s, 9H) EXAMPLE 33 2-. { 3-Methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1 H- benzoimidazoi CLAP: Rt = 6.30. MS (electroaspersion): mass calculated for C23H27F3N4O2, 448.21; m / z found, 449.2 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.93 (s, 1 H), 7.79 (d, J = 8.6 Hz, 1H), 7.69-7.66 (m, 3H), 7.11 (d, J = 9.0 Hz, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.45-3.39 (m, 7H) ), 3.21-3.18 (m, 3H), 3.18 (s, 3H), 2.21-2.17 (m, 2H).

EXAMPLE 34 -Chloro-2-. { 3-chloro-4- [3- (4-methyl-piperazin-1-ii) -propoxy] -phenyl} -6-fluoro-1H-benzoimidazole CLAP: Rt = 6.41. MS (electroaspersion): mass calculated for C21H23CI2FN4O, 436.12; m / z found, 437.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.98 (d, J = 2.3 Hz, 1 H), 7.87 (dd, J = 8.7, 2.3 Hz, 1 H), 7.63 (d, J = 6.4 Hz, 1 H), 7.41 (d, J = 8.8, 1 H), 7.17 (d, J = 8.7 Hz, 1 H), 4.19 (t, J = 5.7 Hz, 2 H), 3.39 (br s, 4 H), 3.25-3.20 (m , 4H), 3.09 (t, 7.3 Hz, 2H), 2.83 (s, 3H), 2.19-2.15 (m, 2H).

EXAMPLE 35 , 6-Dichloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole CLAP: Rt = 6.64.

MS (electroaspersion): mass calculated for C2? H23Cl3N40, 452.09; m / z found, 453.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.74 (s, 2 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.08 (d, J = 2.4 Hz, 1 H), 6.94 (dd, J = 8.8, 2.4 Hz, 1 H), 4.00 (t, J = 5.8 Hz, 2H), 3.43 (br s, 7H), 3.19 (t, J = 7.7 Hz, 2H), 3.05-3.04 (m, 1 H), 2.74 ( s, 3H), 2.10-2.02 (m, 2H).

EXAMPLE 36 -Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole CLAP: Rt = 6.09. EM (electroaspersion): mass calculated for C21H24CI2N4O, 418. 13; m / z found, 419.2 [M + Hf. 1 H NMR (500 MHz, CD 3 OD): 7.76 (d, J = 8.8 Hz, 1 H), 7.73 (dd, J = 1.9, 0.4 Hz, 1 H), 7.69 (dd, J = 8.8, 0.4 Hz, 1 H), 7.47 (dd, J = 8.8, 1.9 Hz, 1 H), 7.23 (d, J = 2.5 Hz, 1 H), 7.09 (dd, J = 8.8.2.5 Hz, 1 H), 4.15 (t, J = 5.9 Hz, 2H), 3.45 (br s, 4H ), 3.34 (br s, 4H), 3.16-3.12 (m, 2H), 2.85 (s, 3H), 2.18-2.12 (m, 2H).

EXAMPLE 37 -Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6-fluoro-1H-benzoimidazole CLAP: Rt = 6.36. MS (electroaspersion): mass calculated for C21H23CI2FN4O, 436.12; m / z found, 437.2 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.78 (d, J = 6.4 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.19 (d , J = 2.5 Hz, 1 H), 7.06 (dd, J = 8.8, 2.5 Hz, 1 H), 4.14 (t, J = 5.8 Hz, 2H), 3.46 (br s, 4H), 3.37 (brs, 3H ), 3.22-3.20 (m, 1 H), 3.18-3.14 (m, 2H), 2.86 (s, 3H), 2.19-2.13 (m, 2H).

EXAMPLE 38 -Chloro-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 6.20. MS (electroaspersion): mass calculated for C 2 H 27 CIN 40, 398.19; m / z found, 399.2 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.88 (dd, J = 8.7, 2.3 Hz, 1 H), 7.83-7.82 (m, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 7.63 (d , J = 8.9 Hz, 1 H), 7.46 (dd, J = 8.7, 1.9 Hz, 1H), 7.14 (d, J = 8.7Hz, 1H), 4.16 (t, J = 6.0Hz, 2H), 3.24 ( br s, 4H), 2.95 (brs, 4H), 2.88-2.85 (m, 2H), 2.77 (s, 3H), 2.26 (s, 3H), 2.11-2.05 (m, 2H).

EXAMPLE 39 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methyl-1H-benzoimidazole CLAP: Rt = 5.93. EM (electroaspersion): mass calculated for C22H27CIN4O, 398. 19; m / z found, 399.3 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 8.10 (d, J = 2.4 Hz, 1 H), 7.97 (dd, J = 8.7, 2.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.48 ( s, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 4.24 (t, J = 5.8 Hz, 2 H), 3.34 (br s, 4 H ), 3.14 (brs, 4H), 3.02-2.99 (m, 2H), 2.80 (s, 3H), 2.45 (s, 3H), 2.18-2.12 (m, 2H).

EXAMPLE 40 ,6-dicIoro-2-. { 3-chloro-4-. { 3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole CLAP: Rt = 6.69. MS (electroaspersion): mass calculated for C21H23CI3N4O, 452.09; m / z found, 453.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.08 (d, J = 2.3 Hz, 1 H), 7.95 (dd, J = 8.7, 2.3 Hz, 1 H), 7.81 (s, 2 H), 7.26 (d, J = 8.8 Hz, 1H), 4.25 (t, J = 5.7 Hz, 2H), 3.55 (br s, 8H), 3.36-3.32 (m, 2H), 2.90 (s, 3H), 2.31-2.25 (m, 2H).

EXAMPLE 41 -Chloro-6-methyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H- benzoimidazole CLAP: Rt = 6.40. MS (electroaspersion): mass calculated for C23H29CIN4O, 412.20; m / z found, 413.2 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.87 (dd, J = 8.6, 2.5 Hz, 1 H), 7.82-7.81 (m, 1 H), 7.69 (s, 1 H), 7.58 (s, 1 H), 7.14 (d, J = 8.7 Hz, 1 H), 4.15 (t, J = 6.0 Hz, 2H), 3.20 (br s, 4H), 2.85 (br s, 4H), 2.83-2.79 (m, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H), 2.08-2.03 (m, 2H).

EXAMPLE 42 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methyl-1 H-benzoimidazole CLAP: Rt = 5.92. MS (electroaspersion): mass calculated for C22H27CIN4O, 398.19; m / z found, 399.3 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.87 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.64 (s, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.23 (dd, J = 8.8.2.4 Hz, 1 H), 4.26 (t, J = 5.8 Hz, 2H), 3.60 (br s , 4H), 3.51 (br s, 4H), 3.31-3.27 (m, 2H), 2.98 (s, 3H), 2.58 (s, 3H), 2.31-2.26 (m, 2H).

EXAMPLE 43 -Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 6.15. MS (electroaspersion): mass calculated for C21H24CI2N4O, 418.13; m / z found, 419.2 [M + H] +. 1 H NMR (500 MHz, CD3OD): 8.07 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.7, 2.3 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.38 (dd, J = 8.7, 1.9 Hz, 1 H), 7.24 (d, J = 8.8 Hz, 1 H), 4.22 (t, J = 5.8 Hz, 2H), 3.42 (br s, 4H), 3.29 (br s.4H), 3.15-3.10 (m, 2H), 2.84 (s, 3H), 2.21-2.15 (m, 2H).

EXAMPLE 44 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1 H-benzoimidazole CLAP: Rt = 6.53. MS (electroaspersion): mass calculated for C22H24CIF3N4O, 452.16; m / z found, 453.2 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 8.12 (d, J = 2.3 Hz, 1 H), 7.99 (dd, J = 8.7, 2.3 Hz, 1 H), 7.90 (s, 1 H), 7.75 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 4.22 (t, J = 5.8 Hz, 2H), 3.37 (br s, 4H) , 3.21 (br s, 4H), 3.08-3.05 (m, 2H), 2.82 (s, 3H), 2.19-2.14 (m, 2H).

EXAMPLE 45 -Chloro-6-fluoro-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole CLAP: Rt = 6.34. MS (electroaspersion): mass calculated for C22H26CIFN4O, 416.18; m / z found, 417.1 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.85 (dd, J = 8.6.2.3 Hz, 1 H), 7.80-7.79 (m, 1 H), 7.72 (d, J = 6.3 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.10 (d, J = 8.7 Hz, 1 H), 4.14 (t, J = 6.0 Hz, 2H), 3.20 (brs, 8H), 2.85-2.81 (, 2H), 2.76 (s, 3H), 2.25 (s, 3H), 2.09-2.04 (m, 2H).

EXAMPLE 46 -Methyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole CLAP: Rt = 6.13. MS (electroaspersion): mass calculated for C23H30N4O, 378.24; m / z found, 379.2 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.87 (d, J = 8.6 Hz, 1 H), 7.82-7.81 (m, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.46 (s, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 1 H), 4.16 (t, J = 6.0 Hz, 2H), 3.29 (brs, 4H), 3.06 (brs, 4H), 2.96-2.93 (m, 2H), 2.79 (s, 3H), 2.46 (s) , 3H), 2.26 (s, 3H), 2.14-2.08 (m, 2H).

EXAMPLE 47 2-3-Chloro-4- [3- (4-metii-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 5.70. MS (electroaspersion): mass calculated for C2? H25CIN40, 384.17; m / z found, 385.2 [M + H] +. H NMR (500 MHz, CD3OD): 8.13 (d, J = 2.3 Hz, 1 H), 8.00 (dd, J = 8.7, 2.3 Hz, 1 H), 7.72-7.67 (m, 2H), 7.53-7.48 ( m, 2H), 7.33 (d, J = 8.8 Hz, 1 H), 4.25 (t, J = 5.9-Hz, 2H), 3.30 (br s, 4H), 3.06 (br s, 4H), 2.96-2.92 (m, 2H), 2.79 (s, 3H), 2.15-2.10 (m, 2H).

EXAMPLE 48 2-. { 3-Methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl-1 H-benzoimidazole CLAP: Rt = 5.89. MS (electroaspersion): mass calculated for C22H28N4O, 364.23; m / z found, 365.2 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.90 (dd, J = 8.5, 2.5 Hz, 1H), 7.85-7.84 (m, 1 H), 7.70-7.66 (m, 2H), 7.52-7.47 (m, 2H) , 7.15 (d, J = 8.6 Hz, 1 H), 4.16 (t, J = 6.0 Hz, 2H), 3.23 (br s, 4H), 2.96 (br s, 4H), 2.87-2.84 (m, 2H) , 2.77 (s, 3H), 2.27 (s, 3H), 2.11-2.05 (m, 2H).

EXAMPLE 49 2-. { 2-Chloro-4- [3- (4-methyl-pi? Erazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole CLAP: Rt = 5.68. MS (electroaspersion): mass calculated for C21H25CIN4O, 384.17; m / z found, 385.3 [M + H] +. 1 H NMR (500'MHz, CD3OD): 7.78 (d, J = 8.8 Hz, 1H), 7.77-7.74 (m, 2H), 7.56-7.53 (m, 2H), 7.27 (d, J = 2.4 Hz, 1 H), 7.12 (dd, J = 8.8.2.4 Hz, 1 H), 4.16 (t, J = 5.9 Hz, 2H), 3.44 (br s, 4H), 3.32 (br s, 4H), 3.14-3.11 (m, 2H), 2.84 (s, 3H), 2.18-2.12 (m, 2H).

EXAMPLE 50 -Chloro-6-fluoro-2-. { 3-methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole CLAP: Rt = 6.15. MS (electroaspersion): mass calculated for C22H26CIFN4O2, 432.17; m / z found, 433.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.75-7.73 (m, 1 H), 7.61-7.58 (m, 2H), 7.52 (d, J = 8.5 Hz, 1 H), 7.09-7.07 (m, 1 H), 4.16 (t, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.48 (br s, 8H), 3.25-3.22 (m, 2H), 2.86 (s, 3H), 2.22-2.19 (m, 2H).

EXAMPLE 51 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methoxy-1H-benzoimidazole CLAP: Rt = 5.85. MS (electroaspersion): mass calculated for C22H27CIN4O2, 414.18; m / z found, 415.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.08 (d, J = 2.3 Hz, 1 H), 7.94 (dd, J = 8.7, 2.3 Hz, 1 H), 7.56 (d, J = 8.9 Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1 H), 7.10 (dd, J = 9.0.2.3 Hz, 1 H), 4.26 (t, J = 5.7 Hz, 2H ), 3.82 (s, 3H), 3.52 (br s, 8H), 3.30-3.26 (m, 2H), 2.88 (s, 3H), 2.29-2.22 (m, 2H).

EXAMPLE 52 -fer-Butyl-2-. { 3,5-dibromo-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole CLAP: Rt = 6.81.

EM (electroaspersion): mass calculated for C25H32Br N4 ?, 562.09; m / z found, 563.1 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 8.31 (s, 2 H), 7.70-7.62 (m, 3 H), 4.17 (t, J = 5.8 Hz, 2 H), 3.37 (br s, 4 H), 3.20 (br s, 4H), 3.18-3.15 (m, 2H), 2.82 (s, 3H), 2.22-2.16 (m, 2H), 1.34 (s, 9H).

EXAMPLE 53 2-. { 2-Methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1H-benzoimidazole CLAP: Rt = 6.34. EM (electroaspersion): mass calculated for C23H27F3N4O2, 448. twenty-one; m / z found, 449.3 [M + Hf. 1 H NMR (500 MHz, CD 3 OD): 8.11-8.08 (m, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1 H), 6.89-6.87 (m, 2H ), 4.28 (t, J = 5.8 Hz, 2H), 4.17 (s, 3H), 3.58 (br s, 4H), 3.49 (br s, 4H), 3.30-3.27 (m, 2H), 2.97 (s, 3H), 2.31-2.25 (m, 2H).

EXAMPLE 54 2-. { 4-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1H-benzoimidazole CLAP: Rt = 6.47. MS (electroaspersion): mass calculated for C22H24CIF3N4O, 452.16; m / z found, 453.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.09 (s, 1 H), 7.93 (d, J = 8.7 Hz, 1H), 7.85-7.80 (m, 2H), 7.29 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 8.8, 2.5 Hz, 1H), 4.20 (t, J = 5.8 Hz, 2H), 3.62 (brs, 8H), 3.40-3.36 (m, 2H), 2.93 (s, 3H), 2.29-2.20 (m, 2H).

EXAMPLE 55 2-. { 3- [3- (4-Metll-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 5.51.

MS (electroaspersion): mass calculated for C21H26N4O, 350.21; m / z found, 351.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.75-7.72 (m, 2 H), 7.70-7.60 (m, 2 H), 7.54-7.51 (m, 3 H), 7.26-7.24 (m, 1 H), 4.16 (t, J = 6.0 Hz, 2H), 3.35 (br s, 4H), 3.19 (br s, 4H), 3.05-3.01 (m, 2H), 2.81 (s, 3H), 2.14-2.10 (m, 2H).

EXAMPLE 56 (2- {3- [4- (4-Methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H -benzoimidazol-5-yl) -phenyl-methanone CLAP: Rt = 6.36. EM (electroaspersion): mass calculated for C29H32N4O2, 468.25; m / z found, 469.3 [M + H] +. H NMR (400 MHz, CD3OD): 8.11 (s, 1 H), 7.90-7.77 (m, 4H), 7.72-7.65 (m, 3H), 7.58-7.52 (m, 3H), 7.23-7.20 (m, 1 H), 4.15 (t, J = 5.7 Hz, 2H), 3.57 (br s, 8H), 3.26-3.21 (m, 2H), 2.95 (s, 3H), 1.96-1.93 (m, 4H). The following compounds in Examples 57-71 were prepared according to the procedures described in Example 2.

EXAMPLE 57 6-Chloro-2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H27CI2N3O, 431.15; m / z found, 432.1 [M + H] +. H NMR (400 MHz, CD3OD): 7.69 (d, J = 8.0 Hz, 1 H), 7.42 (br s, 1 H), 7.14 (d, J = 4.0 Hz, 1 H), 7.07-7.05 (m, 1H), 7.02 (dd, J = 8.0, 4.0 Hz, 1 H), 4.04 (t, J = 8.0 Hz, 2H), 2.95-2.85 (m, 2H), 2.58 (s, 3H), 2.28 (s, 3H), 2.10-2.00 (m, 2H), 1.84-1.75 (m, 4H), 1.46-1.41 (m, 2H), 1.22-1.35 (m, 3H).

EXAMPLE 58 -Fer-Butyl-2-3-chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C26H34CIN30, 439.24; m / z found, 440.2 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.10 (d, J = 2.2 Hz, 1 H), 7.97 (dd, J = 8. 6, 2.2 Hz, 1 H), 7.58 (br s, 1 H), 7.52-7.45 (m, 1 H), 7.36 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1 H), 4.14 (t, J = 6.2 Hz, 2H), 2.93-2.85 (m, 2H), 2.28 (s, 3H), 2.11-2.00 (m, 2H), 1.92-1.83 (m, 2H), 1.82-1.74 (m, 2H), 1.52-1.45 (m, 2H), 1.42-1.20 (m, 12H) .

EXAMPLE 59 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4,5-dimethyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C24H30CIN3O, 411.21; m / z found, 412.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.73-7.63 (m, 1 H), 7.31 (br s, 1 H), 7. 13 (d, J = 2.5 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 7.02 (dd, J = 8.7.2.5 Hz, 1 H), 4. 06 (t, J = 6.3 Hz, 2H), 2.93-2.89 (m, 2H), 2.51 (s, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.00-2.15 (m, 2H), 1.86-1.77 (m, 4H), 1.48-1.42 (m, 2H), 1.35-1.24 (m, 3H).

EXAMPLE 60 -Chloro-6-methyl-2-. { 4- [3- (1-methyl-piperidin-4-y!) - propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 6.84. MS (electroaspersion): mass calculated for C23H28CIN3O, 397.19; m / z found, 398.5 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.95 (d, J = 9.0 Hz, 2H), 7.67 (s, 1H), 7.57 (s, 1 H), 7.12 (d, J = 9.0 Hz, 2H), 4.05 ( t, J = 6.3 Hz, 2H), 3.42 (d, J = 10.4 Hz, 2H), 2.92-2.86 (m, 2H), 2.89 (s, 3H), 2.45 (s, 3H), 1.96-1.93 (m , 2H), 1.82-1.77 (m, 2H), 1.60-1.52 (m, 1 H), 1.45-1.30 (m, 4H).

EXAMPLE 61 -Chloro-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 6.62. EM (electroaspersion): mass calculated for C22H26CIN3O, 383. 18; m / z found, 384.5 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 7.96 (d, J = 9.0 Hz, 2 H), 7.66 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 8.7 Hz, 1 H), 7.42 (dd) , J = 8.7, 1.9 Hz, 1 H), 7.12 (d, J = 9.0 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.43-3.40 (m, 2H), 2.92-2.86 (m , 2H), 2.76 (s, 3H), 1.96-1.93 (m, 2H), 1.82-1.76 (m, 2H), 1.60-1.51 (m, 1 H), 1.46-1.30 (m, 4H).

EXAMPLE 62 -Chloro-6-fluoro-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 6.80. MS (electroaspersion): mass calculated for C22H25CIFN3O, 401.17; m / z found, 402.5 [M + Hf. 1 H NMR (500 MHz, CD 3 OD): 7.93 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 6.3 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 4.03 (t, J = 6.3 Hz, 2H), 3.44-3.40 (m, 2H), 2.92-2.86 (m, 2H), 2.76 (s, 3H), 1.96-1.93 (m , 2H), 1.82-1.76 (m, 2H), 1.60-1.51 (m, 1H), 1.43-1.29 (m, 4H).

EXAMPLE 63 -fer-B util-2-. { 4- [3- (1-methyl-piperidin-4-yl) -pro-poxy] -pheni} - 1 H-benzoimidazole CLAP: Rt = 7.16. MS (electroaspersion): mass calculated for C26H35N3O, 405.28; m / z found, 406.6 [M + Hf. 1 H NMR (500 MHz, CD 3 OD): 8.09 (d, J = 9.0 Hz, 2H), 7.70 (s, 1 H), 7.71 (s, 2H), 7.25 (d, J = 9.0 Hz, 2H), 4.16 (t, J = 6.3 Hz, 2H), 3.58-3.52 (m, 2H), 3.03-2.97 (m, 2H), 2.87 (s, 3H), 2.06-2.03 (m, 2H), 1.93-1.87 (m, 2H), 1.71-1.63 (m, 1 H), 1.57-1.49 (m, 4H), 1.44 (s) , 9H).

EXAMPLE 64 -Methyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole CLAP: Rt = 6.53. EM (electroaspersion): mass calculated for C23H29N3o, 363.23; m / z found, 364.5 [M + H] + .1 H NMR (500 MHz, CD30D): 7.96 (d, J = 9.0 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.47 (s) , 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 9.0 Hz, 2H), 4.05 (t, J = 6.2 Hz, 2H), 3.44-3.41 (m, 2H) , 2.92-2.86 (m, 2H), 2.76 (s, 3H), 2.45 (s, 3H), 1.96-1.92 (m, 2H), 1.82-1.76 (m, 2H), .60-1.50 (m, 1 H), 1.45-1.33 (m, 4H).

EXAMPLE 65 2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -fenii} -1 H-benzoimidazole CLAP: Rt = 6.28. MS (electroaspersion): mass calculated for C22H27N3O, 349.22; m / z found, 350.5 [M + H] +. 1 H NMR (500 MHz, CD 3 OD): 8.00 (d, J = 8.9 Hz, 2H), 7.70-7.66 (m, 2H), 7.51-7.47 (m, 2H), 7.15 (d, J = 8.9 Hz, 2H) , 4.06 (t, J = 6.2 Hz, 2H), 3.43-3.40 (m, 2H), 2.92-2.85 (m, 2H), 2.76 (s, 3H), 1.96-1.93 (m, 2H), 1.82-1.77 (m, 2H), 1.60-1.50 (m, 1 H), 1.45-1.33 (m, 4H).

EXAMPLE 66 6-Chloro-2-. { 2-fluoro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H27CIFN3O, 415.18; m / z found, 416.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.02 (s, 1 H), 7.41 (s, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.85 (m, 2 H), 4.06 (t, J = 6.3 Hz, 2H), 2.93-2.83 (m, 2H), 2.60 (s, 3H), 2.26 (s, 3H), 2.07-1.97 (m, 2H), 1.89-1.71 (m, 4H), 1.49-1.40 (m, 2H), 1.38-1.22 (m, 3H).

EXAMPLE 67 -Fluoro-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1H-benzoimidazole EM (electroaspersion): mass calculated for C23H28F 3O, 381. 22; m / z found, 382.3 [M + Hf. 1 H NMR (400 MHz, CD3OD): 7.61-7.52 (m, 2H), 7.29 (dd, J = 9.1, 2. 3 Hz, 1H), 7.09-7.01 (m, 1 H), 6.96-6.86 (m, 2H), 4.04 (t, J = 6.4 Hz, 2H), 2. 95-2.82 (m, 2H), 2.52 (s, 3H), 2.28 (s, 3H), 2.08-1.96 (m, 2H), 1.88-1.72 (m, 4H), 1.51-1.40 (m, 2H), 1.38-1.19 (m, 3H).

EXAMPLE 68 4-Chloro-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 Hbencimidazole EM (electroaspersion): mass calculated for C23H28CIN3, 397.19; m / z found, 398.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.56 (d, J = 8.5 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.31-7.20 (m, 2 H), 6.93 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 8.5, 2.5 Hz, 1 H), 4.04 (t, J = 6.3 Hz, 2H), 2.94-2.84 (m, 2H), 2.51 (s, 3H), 2.28 (s, 3H), 2.09-1.97 (m, 2H), 1.89-1.72 (m, 4H), 1.52-1.40 (m, 2H), 1.37-1.21 (m, 3H).

EXAMPLE 69 6-Chloro-4-methyl-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C24H30CIN3O, 411.21; m / z found, 412.4 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.54 (d, J = 8.4 Hz, 1 H), 7.42 (br s, 1 H), 7.09-7.05 (m, 1 H), 6.94 (d, J = 2.3 Hz, 1 H), 6.90 (dd, J = 8.4, 2.4 Hz, 1 H), 4. 06 (t, J = 6.3 Hz, 2H), 2.96-2.86 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 2.29 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.75 (, 4H), 1.52-1.43 (m, 2H), 1.38-1.23 (m, 3H).

EXAMPLE 70 -Chloro-2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -6-fluoro-1 H- benzoimidazole EM (electroaspersion): mass calculated for C22H24CI2FN3O, 435.13; m / z found, 436.3 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.78 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 6.6 Hz, 1 H), 7.46 (d, J = 9.3 Hz, 1 H), 7.14 (d , J = 2.4 Hz, 1 H), 7.04 (dd, J = 8.7, 2.5 Hz, 1 H), 4.06 (t, J = 6.4 Hz, 2H), 2.93-2.84 (m, 2H), 2.28 (s, 3H), 2.09-1.96 (m, 2H), 1.87-1.71 (m, 4H), 1.49-1.39 (m, 2H), 1.35-1.22 (m, 3H).

EXAMPLE 71 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -3H-naphtho [1,2-d] imidazole EM (electroaspersion): mass calculated for C26H28CIN3O, 433. 19; m / z found, 434.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.52-8.44 (m, 1 H), 7.97 (d, J = 8.2 Hz, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 7.74 (s, 2 H) , 7.64-7.57 (m, 1 H), 7.53-7.47 (m, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 7.02 (dd, J = 8.6.2.5 Hz, 1 H), 4.01 (t, J = 6.3 Hz, 2H), 2.89-2.78 (m, 2H), 2.25 (s, 3H), 2.03-1.90 (m, 2H), 1.83-1.64 (m, 4H), 1.43-1.33 (m , 2H), 1.33-1.18 (m, 3H). The following compounds in Examples 72-81 were prepared according to the procedures described in Example 1.

EXAMPLE 72 4,6-Dimethyl-2-. { 2-methyl-4- [3- (4-methyi-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.3 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.51 (d, J = 8.5 Hz, 1 H), 7.20 (s, 1H), 6.92-6.70 (m, 3H), 4.07 (t, J = 6.1Hz, 2H), 2.72-2.40 (m, 19H), 2.30 (s, 3H), 2.02-1.98 (m, 2H).

EXAMPLE 73 2-. { 2-CIOR-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl) -4-methyl-1H-benzoimidazole MS (electroaspersion): mass calculated for C22H27CIN4O, 398. 19; m / z found, 399.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.72-7.67 (m, 1 H), 7.41 (s, 1 H), 7. 18-7.13 (m, 2H), 7.07-7.02 (m, 2H), 4.13 (t, J = 6.1Hz, 2H), 2.80-2.40 (m, 13H), 2.30 (s, 3H), 2.05-1.98 (m, 2H).

EXAMPLE 74 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-fluoro-4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H26CIFN?, 416. 18; m / z found, 417.1 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.76-7.65 (brs, 1H), 7.47-7.33 (br s, 1 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.07-7.00 (m, 2H) , 4.13 (t, J = 6.1 Hz, 2H), 2.68-2.40 (m, 13H), 2.32 (s, 3H), 2.08-1.97 (m, 2H).

EXAMPLE 75 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl) -3H-naphtho [1,2-d] imidazole EM (electroaspersion): mass calculated for C25H27ClN4 ?, 434.19; m / z found, 435.2 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 8.49 (s, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.74-7.68 (m, 3 H), 7.60-7.55 (m, 1 H), 7.48. -7.43 (m, 1 H), 7.07 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.7, 2.5 Hz, 1 H), 3.92 (t, J = 6.1 Hz, 2H), 2.62- 2.30 (m, 10H), 2.22 (s, 3H), 1.89-1.81 (m, 2H).

EXAMPLE 76 6- { 2-Chloro-4- [3- (4-methyl-piperazi n-1-yl) -propoxy] -fenif} -5H- [1, 3] dioxolo [A ', 5': A, 5] beñzo [i, 2-d] imidazole EM (electroaspersion): mass calculated for C22H25ClN403, 428.16; m / z found, 429.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.74 (d, J = 8.7 Hz, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 7.07-6.97 (m, 3 H), 5.98 (s, 2 H), 4.11 (t, J = 6.2 Hz, 2H), 2.74-2.36 (m, 10H), 2.31 (s, 3H), 2.07-1.96 (m, 2H).

EXAMPLE 77 6-Chloro-2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1 hibenzoimidazole EM (electroaspersion): mass calculated for C23H28CI2N4O, 446.16; m / z found, 447.1 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.72 (d, J = 8.6 Hz, 1 H), 7.44 (brs, 1 H), 7.18 (d, J = 2.5 Hz, 1 H), 7.10-7.08 (m, 1 H), 7.05 (dd, J = 8.7, 2.5 Hz, 1 H), 4.14 (t, J = 6.1 Hz, 2H), 2.83-2.78 (m, 4H), 2.75-2.69 (m, 6H), 2.60 ( s, 3H), 2.39 (s, 3H), 2.04-1.96 (m, 2H), 1.90-1.84 (m, 2H).

EXAMPLE 78 2-. { 3-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1 H- benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN40, 412.20; m / z found, 413.2 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.19 (d, J = 2.2 Hz, 1 H), 8.04 (dd, J = 8.6, 2.2 Hz, 1 H), 7.42 (d, J = 7.9 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 7.18-7.11 (m, 1 H), 7.04 (d, J = 7.2Hz, 1 H), 4.19 (t, J = 6.0 Hz, 2H), 2.84-2.66 (m, 10H), 2.62 (s, 3H), 2.36 (s, 3H), 2.08-1.98 (m, 2H), 1.89-1.82 (m, 2H).

EXAMPLE 79 4,6-Dimethyl-2-. { 3- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C25H34N4O, 406.27; m / z found, 407.2 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.75-7.70 (m, 1 H), 7.69-7.64 (d, J = 7.7 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.23 (br s, 1 H ), 7.04 (m, 1 H), 6.90 (br s, 1 H), 4.12 (t, J = 6.2 Hz, 2 H), 2.83-2.75 (m, 4 H), 2.73-2.65 (m, 4 H), 2.63 -2.54 (m, 5H), 2.44 (s, 3H), 2.35 (s, 3H), 1.89-1.79 (m, 4H), 1.76-1.68 (m, 2H).

EXAMPLE 80 -Chloro-2-. { 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole EXAMPLE 81 2-. { 4- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole EXAMPLE 82 . { 2- (6-Chloro-4-methyl-1 H -benzoimidazol-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzyl} -dimethyl-amine A. 4-Bromo-3-dimethylaminomethyl-phenol. 2-Bromo-5-hydroxy-benzaldehyde (5.0 g, 24.9 mmol, 1.0 equiv.) And 2.0 M dimethylamine in THF (31 ml, 62 mmol, 2.5 equiv.) Were stirred in dichloroethane (50 ml) at room temperature for 1.0 hr. Sodium triacetoxyborohydride (15.8 g, 75 mmol, 3.0 equiv.) Was added, and the mixture was stirred for 3.0 hr, then it was poured into saturated aqueous NaHCO3. The aqueous mixture was extracted three times with chloroform and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by method 2 to give 2.12 g (38%) of the title compound. 1 H NMR (400 MHz, CD3OD): 7.36 (dd, J = 8.6.1.8 Hz, 1 H), 6.91-6.90 (m, 1 H), 6.67-6.62 (m, 1 H), 3.53 (d, J = 1.3 Hz, 1 H), 2.30 (m, 6H). B. { 2-Bromo-5-f3- (1-methyl-piperidin-4-yl) -propoxp-benzyl) -dimethyl-amine. To a solution of 3- (1-methyl-piperidin-4-yl) -propan-1-ol (989 mg, 6.3 mmol, 1.0 equiv.) And methanesulfonyl chloride (683 μl, 8.8 mmol, 1.4 equiv.) In dichloromethane (12 ml) at 0 ° C was added triethylamine (1.57 m !, 11.3 mmoles, 1.8 equiv.). The reaction mixture, which was allowed to warm to room temperature, was stirred for 12 hr and then emptied into saturated aqueous NaHCO3. The aqueous mixture was extracted three times with 10% 2-propanol in chloroform and the extract was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (21 ml) and 4-bromo-3-dimethylaminomethyl-phenol (1.44 g, 6.3 mmol, 1.0 eq.) And cesium carbonate (4.1 g, 12.6 mmol, 2.0 equiv.) Were added. The mixture was stirred at room temperature for 12 hr, then heated at 40 ° C for 2.0 hr, then at 50 ° C for 1.0 hr, and finally at 65 ° C for 1.5 hr. The mixture was poured into saturated aqueous NaHCO3 and extracted twice with ethyl acetate and once with chloroform. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by method 2 gave 814 mg (40%) of the title compound. 1 H NMR (400 MHz, CD 3 OD): 7.45 (d, J = 8.8 Hz, 1 H), 7.05 (d, J = 3.1 Hz, 1 H), 6.78 (dd, J = 8.8.3.1 Hz, 1 H), 3.98 (t, J = 6.4 Hz, 2H), 3.58 (s, 2H), 2.93-2.86 (m, 2H), 2.31 (s, 6H), 2.29 (s, 3H), 2.10-1.98 (m, 2H) , 1.86-1.73 (m, 4H), 1.49-1.22 (m, 5H). O (2- (6-Chloro-4-methyl-1 H-benzoimidazol-2-yl) -5-r3-1-methyl-piperidin-4-yl) -propoxyl-benzyl-dimethyl-amine. To a solution of. { 2-bromo-5- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzyl} dimethyl-amine (801 mg, 2.2 mmol, 1.0 equiv.) in THF (10 mL) at -78 ° C, 1.7 M tert-butyl-lithium in pentane (3.83 mL, 6.5 mmol, 3.0 equiv.) was added and The solution was stirred for 15 min. The solution was then warmed to 0 ° C, stirred for 5 min, and then re-cooled to -78 ° C. DMF (1.68 ml, 21.7 mmol, 10.0 equiv.) Was added and the mixture was stirred for 30 min. Water (1.0 ml) was added and the mixture was poured into saturated aqueous NaHCO3. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The residue was partially purified by method 2 to give 221 mg of a mixture of 2-dimethylaminomethyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzaldehyde and some other unidentified products. Crude dimetlaminomethyl-1- [3- (1-methyl-piperidin-4-yl) -propoxy-benzaldehyde (110 mg) was dissolved in DMF and 5-chloro-3-methyl- benzene-1, 2-diamine (54 mg, 0.34 mmole) and Na2S205 (85 mg, 0.45 mmole). The mixture was heated to 90 ° C and stirred for 3 hr. The reaction mixture was purified by method 2 to give 15.2 mg of the title compound. EM (electroaspersion): mass calculated for C26H35CIN 0, 454.25; m / z found, 455.5 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.07 (d, J = 8.6 Hz, 1 H), 7.47-7.42 (m, 1 H), 7.07-6.97 (m, 3H), 4.04 (t, J = 6.4 Hz, 2H), 3.58 (s, 2H), 2.93-2.82 (m, 2H), 2.56 (s, 3H), 2.43 (s, 6H), 2.27 (s, 3H), 2.06-1.93 (m, 2H), 1.87 -1.70 (m, 4H), 1.49-1.40 (m, 2H), 1.36-1.21 (m, 3H).

EXAMPLE 83 . { 2- (5-Fluoro-4-methyl-1 H-benzoimidazol-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzyl} dimethyl amine The title compound was prepared as described in example 77. MS (electroaspersion): mass calculated for C 26 H 35 FN 4 O, 438.28; m / z found, 439.5 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.06 (d, J = 8.6 Hz, 1 H), 7.43-7.40 (m, 1 H), 7.06 (dd, J = 8.6.2.6 Hz, 1H), 7.03-6.95 (m, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.59 (s, 2H), 2.89 -2.86 (m, 2H), 2.49 (s, 3H), 2.44 (s, 6H), 2.27 (s, 3H), 2.07-1.96 (m, 2H), 1.89-1.72 (m, 4H), 1.51-1.41 (m, 2H), 1.39-1.22 (m, 3H).

EXAMPLE 84 4-. { 3- [4- (6-Chloro-4-methyl-1 H -benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} - [1, 4] diazepan-5-one A. 4- (3-Iodo-propoxy ') - 2-methyl-benzaldehyde. 1-Bromo-3-chloropropane (5.03 g, 32.0 mmol, 1.0 equiv.) Was added to a solution of 2-methyl-4-hydroxybenzaldehyde (4.35 g, 32.0 mmol, 1.0 equiv.) And K2C03 (8.8 g, 64. 0 mmol, 2.0 equiv.) In acetonitrile (75 ml). The mixture was heated at 65 ° C for 16 hr, then cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 10% ethyl acetate in hexanes) to give 5.58 g (82%) of 4- (3-chloro-propoxy) -2-methyl- benzaldehyde To a reflux solution of 4- (3-chloro-propoxy) -2-methyl-benzaldehyde in acetone (100 ml), Kl (58 g) was added in portions for 3 days. The mixture was cooled to room temperature and water was added. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to give 6.13 g (77%) of the title compound. 1 H NMR (400 MHz, CD 3 OD): 10.1 (s, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 6.84 (dd, J = 8.6.2.5 Hz, 1 H), 6.74 (d, J = 2.2 Hz, 1 H), 4.11 (t, J = 5.8 Hz, 2H), 3.36 (t, J = 6.7 Hz, 2H), 2.65 (s, 3H), 2.29 (m, 2H). B. 4-. { 3-f4- (6-Chloro-4-methyl-1H-benzoimidazol-2-yl) -3-methyl-phenoxy-1-propylH, 4] diazepan-5-one. To a stirred solution of 5-oxo- [1, 4] diazepan-1-carboxylic acid fer-butyl ester (3.0 g, 14.0 mmol, 1.0 equiv.) In DMF (45 mL) at room temperature was added sodium hydride. to 60% (560 mg, 14.0 mmol, 1.0 equiv.). After stirring for 30 min, 4- (3-iodo-propoxy) -2-methyl-benzaldehyde (4.26 g, 14.0 mmol, 1.0 equiv.) Was added as a solution in DMF (5 mL). The mixture was stirred for 16 hr and then it was poured into water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was partially purified by column chromatography (silica gel, 5-50% ethyl acetate in hexanes) to give 4- [3- (4-formyl-3-methyl-phenoxy) - tert-butyl ester. propyl] -5-oxo- [1,4] diazepane-1-carboxylic acid as a mixture with some unidentified products. This doped mixture (200 mg), 5-chloro-3-methyl-benzene-1,2-diamine (80.1 mg), and Na2S20 (97 mg) were stirred in DMF (1.0 ml) at 90 ° C for 3 hr. After cooling to room temperature, the reaction mixture was loaded on silica gel and purified by method 2 to give 4-tert-butyl ester. { 3- [4- (6-chloro-4-metii-1 H-benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} -5-oxo- [1,4] diazepane-1-carboxylic acid as a mixture with some unidentified products. This mixture was dissolved in dichloromethane (1.0 ml) and TFA (1.0 ml) and stirred at room temperature for 1 hr. The reaction mixture was loaded onto silica gel and purified by method 2 to give 91.0 mg (42%) of the title compound. MS (electroaspersion): mass calculated for C23H27CIN4O2, 426.18; m / z found, 427.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.55 (d, J = 8.5 Hz, 1 H), 7.42 (br s, 1 H), 7.09-7.06 (m, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.93 (dd, J = 8.5.2.5 Hz, 1 H), 4.10 (t, J = 6.1 Hz, 2H), 3.67-3.56 (m, 4H), 2.98-2.89 (m, 4H), 2.72 -2.66 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.12-2.01 (m, 2H).

EXAMPLE 85 4-. { 3- [4- (5-tert-Butyl-1 H-benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} -1-methyl- [1,4] diazepan-5-one 4-. { 3- [4- (6-Chloro-4-methyl-1 H -benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} - [1, 4] diazepan-5-one (95 mg, 0.22 mmol, 1.0 equiv.) And 37% aqueous formaldehyde (35 μl, 0.44 mmol, 2.0 equiv.) Were stirred in dichloroethane at room temperature for 1.0 hr. Sodium triacetoxyborohydride (139 mg, 0.66 mmol, 3.0 equiv.) Was added, and the mixture was stirred for 1.0 hr then was poured into saturated aqueous NaHCO3. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by method 2 to give 34 mg (35%) of the title compound. MS (electroaspersion): mass calculated for C27H36N4Δ2, 448.28; m / z found, 449.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.62 (br s, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.38 (dd, J = 8.6.1.7 Hz, 1 H), 6.95 (d, J = .2.3 Hz, 1 H), 6.92 (dd, J = 8.5, 2.5 Hz, 1 H), 4.09 (t, J = 6.0 Hz, 2H), 3.65-3.59 (m, 4H), 2.73-2.59 (m, 6H), 2.52 (s, 3H), 2.38 (s, 3H), 2.11-2.02 (m, 2H) .1.43 (s, 9H).

EXAMPLE 86 -tert-Butyl-2-. { 2-methyl-4- [3- (2-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole The title compound was prepared as described in Example 84, using 3-methyl-piperazine-1-carboxylic acid tert-butyl ester in place of 5-oxo- [1, 4] diazepane-1-carboxylic acid. MS (electroaspersion): mass calculated for C 26 H 36 N 4 O, 420.29; m / z found, 421.5 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.66-7.49 (m, 3 H), 7.38 (dd, J = 8.6, 1.8 Hz, 1 H), 6.95 (d, J = 2.2 Hz, 1 H), 6.91 (dd, J = 8.4, 2.5 Hz, 1 H), 4.12 (t, J = 6.2 Hz, 2H), 3.10-2.82 (m, 5H), 2.60-2.32 (m, 7H), 2.09-1.89 (m, 2H), 1.43 (s, 9H), 1.10 (d, J = 6.0 Hz, 3H).

EXAMPLE 87 -ter-Butii-2-. { 2-methyl-4- [3- (2-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H- benzoimidazole The title compound was prepared from 5-tert-butyl-2-. { 2-methyl-4- [3- (2-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole according to the method described in Example 85. MS (electroaspersion): mass calculated for C27H38N4O, 434.30; m / z found, 435.5 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.69-7.47 (m, 3H), 7.38 (dd, J = 8.6, 1. 9 Hz, 1 H), 6.95 (d, J = 2.3 Hz, 1 H), 6.91 (dd, J = 8.5, 2.4 Hz, 1 H), 4.11 (t, J = 6.2 Hz, 2H), 3.10-2.94 (m, 2H), 2.84-2.70 (m, 2H), 2.56-2.39 (m, 6H), 2.31-2.19 (m, 4H), 2.09-1.88 (m, 3H), 1.43 (s, 9H), 1.12 (d, J = 6.3 Hz, 3H).

EXAMPLE 88 6-Chloro-4-methyl-2- [2-methyl-4- (3-piperidin-4-yl-propoxy) -phenyl] -1H-benzoimidazole To a solution of 3-hydroxy-tert-butyl ester -propyl) -piperidine-1-carboxylic acid (4.00 g, 16.4 mmol, 1.0 equiv.) and triethylamine (3.40 mL, 24.6 mmol, 1.5 equiv.) in dichloromethane at 0 ° C methanesulfonyl chloride (1.53 mL, 19.7 mmol. , 1.2 equiv.). The solution was warmed to room temperature and stirred for 1.0 hr, then it was poured into saturated aqueous NaHC 3. The aqueous mixture was extracted three times with chloroform and the combined extracts were dried (Na2SO), filtered and concentrated. The residue was subjected to column chromatography (silica gel, 10% methanol in dichloromethane). The partially purified 4- (3-methanesulfony! Oxy-propyl) -piperidin-1-carboxylic acid fer-butyl ester (500 mg, 1.56 mmol, 1.0 equiv.) Was stirred with 4-hydroxy-2-methyl-benzaldehyde ( 212 mg, 1.56 mmol, 1.0 equiv.) And cesium carbonate (1.01 g, 3.12 mmol, 2.0 equiv.) In acetonitrile at room temperature for 4 days. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The crude material was partially purified by column chromatography (silica gel, 25% ethyl acetate in hexanes). 4- [3- (4-formyl-3-methyl-phenoxy) -propyl] -piperidin-1-carboxylic acid tert-butyl ester (146 mg, 0.41 mmol, 1.0 equiv.), 5-chloro-3-methyl -benzene-1, 2-diamine (63 mg, 0.41 mmol, 1.0 equiv.) and Na2S 05 (100 mg, 0.53 mmol), 1.3 equiv.) Were stirred at 90 ° C in DMF for 2.5 hr. The mixture was cooled to room temperature and water (75 ml) was added causing a brown precipitate to form. The ter-butyl ester of 4-acid. { 3- [4- (6-Chloro-4-methyl-1 H -benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} Solid pyridine-1-carboxylic acid was collected by filtration, dissolved in a solution of dichloromethane (2.0 ml) and trifluoroacetic acid (1.0 ml), and stirred at room temperature for 1.5 hr. The reaction mixture was loaded directly onto silica gel and purified according to method 2, which gave 52.1 mg of the title compound. EM (electroaspersion): mass calculated for C23H28ClN30, 397.19; m / z found, 398.3 [M + Hf. H NMR (400 MHz, CD3OD): 7.55 (d, J = 8.4 Hz, 1H), 7.42 (brs, 1H), 7.10-7.07 (m, 1H), 6.96-6.95 (m, 1H), 6.91 (dd, J = 8.5, 2.4 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.45-3.39 (m, 2H), 3.06-2.96 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.07-1.99 (m, 2H), 1.93-1.84 (m, 2H), 1.76-1.64 (m, 1 H), 1.59-1.50 (m, 2H), 1.48-1.36 (m, 2H).

EXAMPLE 89 -Fluoro-4-methyl-2- [2-metii-4- (3-piperidin-4-yl-propoxy) -phenyl] -1 H -benzoimidazole The title compound was prepared as described in the example 88. MS (electroaspersion): mass calculated for C23H28FN30, 381.22; m / z found, 382.4 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.56 (d, J = 8.5 Hz, 1H), 7.44-7.38 (m, 1 H), 7.09-7.02 (m, 1 H), 6.96 (d, J = 2.3 Hz, 1 H), 6.91 (dd, J = 8.4, 2.5 Hz, 1 H), 4.09 (t, J = 6.2 Hz, 2H), 3.44-3.36 (m, 2H), 3.06-2.95 (m, 2H), 2.52 (d, J = 1. 6 Hz, 3H), 2.50 (s, 3H), 2.08-1.98 (m, 2H), 1.94-1.83 (m, 2H), 1.77-1.65 (m, 1 H), 1.59-1.50 (m, 2H), 1.48-1.35 (m, 2H).

EXAMPLE 90 6-Chloro-2-. { 4- [3- (1-ethyl-piperidin-4-yl) -propoxy] -2-methyl-phenyl} -4-methyl-1H-benzoimidazoi The title compound was prepared as described in Example 85, using acetaldehyde instead of aqueous formaldehyde. EM (electroaspersion): mass calculated for C25H32CIN3 ?, 425.22; m / z found, 426.4 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.53 (d, J = 8.5 Hz, 1 H), 7.41 (br s, 1 H), 7.09-7.04 (m, 1 H), 6.93 (d, J = 2.2 Hz, 1 H), 6.89 (d, J = 8.4, 2.4 Hz, 1 H), 4.04 (t, J = 6.3 Hz , 2H), 3.05-2.94 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 2.45 (q, J = 7.2 Hz, 2H), 2.05-1.94 (m, 2H), 1.89-1.74 (m, 4H), 1.50-1.21 (m, 5H), 1.13 (t, J = 7.2 Hz, 3H).

EXAMPLE .0 91 . { 2- [3-Chloro-4- (4-methyl-1 H-benzoimidazol-2-yl) -phenoxy] -ethyl} -methyl- (1-methyl-piperidin-4-yl) -amine A.4- (2-Bromo-ethoxy) -2-chloro-benzaldehyde. 1, 2-Dibromoethane (5.5 ml, 64.0 mmol, 5.0 equiv.) Was added to a mixture of 2-chloro-4-hydroxy-benzaldehyde (2.0 g, 12.8 mmol, 1.0 equiv.) And K2C03 (4.0 g, 29.0 mmol, 2. 25 equiv.) In acetonitrile (13 ml). The mixture was heated to reflux for 16 hr, cooled to room temperature, and filtered through diatomaceous earth.

The filtrate was concentrated to give crude product, which was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to give 2.28 g (72%) of the title compound. 1 H NMR (400 MHz, CD 3 OD): 10.3 (d, J = 0.7 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 7.06 (ddd) , J = 8.8, 2.5, 0.7 Hz, 1 H), 4.48-4.42 (m, 2H), 3.78-3.74 (m, 2H). B.2-Chloro-4- (2- [methyl-1-methyl-piperidin-4-i0-amino-1-ethoxy) -benzaldehyde. To a solution of 4- (2-bromo-ethoxy) -2-chloro-benzaldehyde (1.24 g, 5.0 mmol, 1.0 equiv.) And methyl- (1-methyl-piperidin-4-yl) -amine (1.28 g, 10.0 mmol, 2.0 equiv.) In 1 -butanol was added K2CO3 (2.10 g, 15 mmol, 3.0 equiv.) And the solution was heated to 90CC. After being stirred for 16 hr, the mixture was poured into water and extracted twice with ethyl acetate. The combined extracts were dried (Na 2 SO 4), filtered and concentrated. The residue was purified by method 2 to give 467 mg (30%) of the title compound. 1 H NMR (400 MHz, CD 3 OD): 10.3 (s, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 7.05 (dd, J = 8.8, 2.4 Hz, 1 H), 4.21 (t, J = 5.5 Hz, 2 H), 3.00-2.88 (m, 4H), 2.57-2.47 (m, 1H), 2.41 (s, 3H), 2.29 (s, 3H), 2.11-2.01 (m, 2H), 1.91-1.82 (m, 2H), 1.68-1.58 (m, 2H). C. { 2-R3-Chloro-4- (4-methyl-1 H -benzoimidazol-2-yl) -phenoxy-ethyl) -methyl- (1-methyl-piperidin-4-yl) -amine. This compound was prepared by the method described in general procedure 3 using 2-chloro-4-. { 2- [Methyl- (1-methyl-piperidin-4-yl) -amino] -ethoxy} -benzaldehyde (62.2 mg, 0.20 mmol, 1.0 equiv.), 3-methyl-benzene-1,2-diamine (26 mg, 0.20 mmol, 1.0 equiv.), and Na2S205 (50 mg, 0.26 mmol, 1.3 equiv.) . Purification by method 2 gave 29 mg (35%) of the title compound. MS (electroaspersion): mass calculated for C23H29CIN4O, 412.20; m / z found, 413.4 [M + H] +. H NMR (400 MHz, CD3OD): 7.73 (d, J = 8.6 Hz, 1 H), 7.49-7.40 (m, 1 H), 7.22-7.14 (m, 2H), 7.11-7.04 (m, 2H), 4.18 (t, J = 5.5 Hz, 2H), 3.00-2.92 (m, 4H), 2.62 (s, 3H), 2.56-2.48 (m, 1 H), 2.41 (s, 3H), 2.28 (s, 3H) ), 2.11-1.99 (m, 2H), 1.92-1.81 (m, 2H), 1.70-1.55 (m, 2H).

EXAMPLE 92 6-Chloro-4-methyl-2-. { 2-methyl-4- [2- (1-methyl-piperidin-4-yloxy) -ethoxy] -phenyl} -1H- benzoimidazole A. Toluen-4-sulfonate of 4-22- (4-formyl-3-methyl-phenoxy) -ethoxyl-1-methyl-piperidinium. To a solution of 1,4-dioxa-8-aza-espyro [4.5] decane (1.0 g, 7.0 mmol, 1.0 equiv.) In toluene (20 ml) at 0 ° C was added 1.0 M diisobutylaluminum hydride in hexane ( 20 ml, 20 mmol, 2.9 equiv.). The solution was heated to 80 ° C and stirred for 12 hr. Methanol (20 ml), saturated aqueous sodium potassium tartrate (20 ml) and 10% 2-propanol in chloroform (100 ml) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 ml). The combined extracts were dried (Na2SO4), filtered and concentrated to provide crude 2- (piperidin-4-yloxy) -ethanol as a white solid. The solid was dissolved in dichloroethane (20 ml) and 37% aqueous formaldehyde (0.60 ml, 6.9 mmol) was added. After being stirred for 30 mln, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 hr. The reaction mixture was diluted with saturated aqueous NaHCO3 (20 ml) and extracted six times with 10% 2-propanol in chloroform (80 ml). The combined extracts were dried (Na 2 SO 4), filtered and concentrated to give 2- (1-methyl-piperidin-4-yloxy) -ethanol. The residue was dissolved in dichloromethane, cooled to 0 ° C, and pyridine (463 gel, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to room temperature and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by method 2. The resulting material was added 2-ester (1-methyl-piperidin-4-yloxy) -ethyl toluene-4-sulfonic acid to a mixture of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100 ° C and stirred for 16 hr. After cooling to room temperature, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by method 2 to give 409 mg of the title compound. 1 H NMR (400 MHz, CD 3 OD): 10.10 (s, 1 H), 7.80 (d, J = 8.6 Hz, 1 H), 7.72 (d, J = 8.2 Hz, 2 H), 7.26 (d, J = 7.9 Hz , 2H), 6.96 (dd, J = 8.6, 2.4 Hz, 1 H), 6.88 (d, J = 2.1 Hz, 1 H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1 H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07 -1.83 (m, 4H). E 6-Chloro-4-methyl-2- (2-methyl-4-r 2 - (1-methyl-piperidin-4-yloxy) -ethoxyl-phenyl} -1-H-benzoimidazole This compound was prepared by the method described in general procedure 3 using toluene-4-sulfonate of 4- [2- (4-formyl-3-methy1-phenoxy) -ethoxy] -1-methyl-pperiodinium (47.5 mg , 0.1 1 mmol, 1.0 equiv.), 5-chloro-3-methyl-benzene-1,2-diamine (27 mg, 0.17 mmol, 1.6 equiv.), And Na2S205 (42 mg, 0.22 mmol, 2.1 equiv. The purification by method 2 gave 20 mg (46%) of the title compound: MS (electroaspersion): mass calculated for C23H28CIN3? 2, 413.19, m / z found, 414.3 [M + H] +. 1H NMR (400 MHz, CD3OD): 7.55 (d, J = 8.5 Hz, 1 H), 7.42 (br s, 1 H), 7.08-7.05 (m, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 8.5, 2.5 Hz, 1 H), 4.21-4.17 (m, 2H), 3.88-3.83 (m, 2H), 3.57-3.47 (m, 1 H), 2.81-2.67 (m, 2H) ), 2.59 (s, 3H), 2.50 (s, 3H), 2.33-2.20 (m, 5H), 2.02-1.90 (m, 2H), 1.76-1.60 (m, 2H).

EXAMPLE 93 6-Chloro-4-methyl-2-. { 2-methyl-4- [3- (1-metii-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -phenyl} -1H-benzoimidazole A. 3- (1-Methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propan-1-ol. To a solution of 4- (3-hydroxy-propyl) -1-methyl-pyridinium iodide (28 g, 100.4 mmol, 1.0 equiv.) In ethanol (200 ml) at 0 ° C was added sodium borohydride (5.7 g. , 151 mmoles, 1.5 equiv.). The reaction mixture, which was allowed to warm to room temperature, was stirred for 30 min and then emptied into water. The aqueous solution was extracted with ethyl acetate and the extract was dried (Na 2 SO 4), filtered and concentrated to give 15.2 g (97%) of the title compound. 1 H NMR (400 MHz, CD3OD): 5.46-5.41 (m, 1 H), 3.56 (t, J = 6.6 Hz, 2H), 2.98-2.91 (m, 2H), 2.60 (t, J = 5.9 Hz, 2H ), 2.35 (s, 3H), 2.21-2.14 (m, 2H), 2.12-2.04 (m, 2H), 1.71-1.62 (m, 2H). B. 2-Methyl-4-r3 (1-methyl-1,2,3,6-tetrahydro-pyridin-4-p-propoxy-benzaldehyde.) To a solution of 3- (1-methyl-1, 2, 3,6-tetrahydro-pyridin-4-yl) -propan-1-ol (2.24 g, 14.5 mmol, 1.0 equiv.) And pyridine (1.64 mL, 20.2 mmol, 1.4 equiv.) In dichloromethane (50 mL) at 0 ° C p-toluenesulfonyl chloride (3.85 g, 20.2 mmol, 1.4 equiv.) Was added The reaction mixture, which was allowed to warm to room temperature, was stirred for 12 hr and then emptied into water. Extraction with dichloromethane and the extract was dried (Na2SO4), filtered and concentrated The residue was subjected to column chromatography on silica gel (10% methanol in dichloromethane) and the resulting oil was added to a mixture of 4 hydroxy-2-methyl-benzaldehyde (639 mg, 4.69 mmol) and K2CO3 (1.62 g, 11.7 mmol) in DMF and heated to 100 ° C. After being stirred for 16 h, the mixture was allowed to cool to room temperature and was heated to room temperature. filtered through a diatomaceous earth pad The diatomaceous earth was rinsed with ethyl acetate, and the filtrate was concentrated. The residue was purified by method 2 to give 356 mg (9%) of the title compound. 1 H NMR (400 MHz, CD 3 OD): 10.1 (s, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 6.92 (dd, J = 8.6.2.4 Hz, 1 H), 6.84 (d, J = 2.1 Hz, 1 H), 5.49-5.43 (m, 1H), 4.09 (t, J = 6.3 Hz, 2H), 2.97-2.91 (m, 2H), 2.65-2.57 (m, 5H), 2.35 (s, 3H), 2.25-2.16 (m, 4H), 1.99-1.88 (m, 2H). C.6-Chloro-4-methyl-2-. { 2-methyl-4-r4- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy-1-phenyl) -1 H -benzoimidazole. This compound was prepared by the method described in general procedure 3 using 2-methyl-4- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -benzaldehyde (50 mg, 0.18 mmol, 1.0 equiv.), 5-chloro-3-methyl-benzene-1,2-diamine (29 mg, 0.18 mmol, 1.0 equiv.), and Na2S205 (45.2 mg, 0.24 mmol, 1.3 equiv.). Purification by method 2 gave 15.7 mg (21%) of the title compound. EM (electroaspersion): mass calculated for C24H28CIN30, 409. 19; m / z found, 410.4 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.53 (d, J = 8.5 Hz, 1 H), 7.41 (br s, 1 H), 7.08-7.04 (m, 1 H), 6.93 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.5, 2.5 Hz, 1 H), 5.49-5.44 (m, 1 H), 4.04 (t, J = 6.3 Hz, 2H), 2.96-2.91 (m, 2H), 2.64-2.56 (m, 5H), 2.49 (s, 3H) , 2.35 (s, 3H), 2.28-2.16 (m, 4H), 1.96-1.88 (m, 2H).

EXAMPLE 94 -Fluoro-4-methyl-2-. { 2-methyl-4- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pheni !} -1H-benzoimidazole The title compound was prepared as described in example 93. MS (electroaspersion): mass calculated for C24H28FN30, 393. 22; m / z found, 394.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.54 (d, J = 8.5 Hz, 1 H), 7.39 (br, 1 H), 7.05-6.95 (m, 1 H), 6.94 (d, J = 2.4 Hz, 1 H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 5.50- 5.46 (m, 1H), 4.06 (t, J = 6.3 Hz, 2H), 2.99-2.94 (m, 2H), 2.65- 2.59 (m, 2H), 2.53-2.47 (m, 6H), 2.36 (s, 3H), 2.27-2.18 (m, 4H), 1.98-1.90 (m, 2H).

EXAMPLE 95 6-Fluoro-7-methyl-2-. { 3- [4- (1-methyl-p.peridin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole A.3-r4- (1-Methyl-piperidin-4-i0-butoxyfl-benzonitrile 4- (1-Methyl-piperidin-4-yl) -butan-1-ol (0.747 g, 4.37 mmoles, 1.0 equiv.), 3-hydroxy-benzonitrile (0.52 g, 4.37 mmol, 1.0 equiv.), and polymer-supported triphenylphosphine (2.3 g, 8.73 mmol, 2.0 equiv.) were suspended in THF (40 ml). The mixture was stirred under N2 and cooled to 0 ° C. Diisopropyl azodicarboxylate (1.72 ml, 8.73 mmol, 2.0 equiv.) was added dropwise by syringe.

After 6 hr, the mixture was filtered and concentrated. The resulting crude oil was purified by method 2 to give 0.84 g (71%) of the title compound. MS (electroaspersion): mass calculated for C17H24N2O, 272.19; m / z found, 273.4 [M + Hf. 1 H NMR (400 MHz, CDCl 3): 7.38-7.33 (m, 1 H), 7.24-7.20 (m, 1H), 7. 14-7.09 (m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 2.88-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73 ( m, 2H), 1.72-1.64 (m, 2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H). B. 3-Ib- (1-methyl-piperidin-4-yl) -butoxy-1-benzaldehyde. To a stirred solution of 3- [4- (1-methyl-piperidn-4-yl) -butoxy] -benzonitrile (0.84 g, 3.09 mmol, 1.0 equiv.) In toluene (5.0 ml) at 0 ° C 1.5 M diisobutylalumino hydride in toluene (4.63 ml, 4.63 mmol, 1.5 equiv.) Was added. After 3 hr, methanol (9.0 ml) and 1.0 M H2SO4 (10 ml) were added dropwise. After stirring for 30 min, 1.0 M NaOH (10 mL) was added, followed by saturated aqueous sodium potassium tartrate (40 mL) and dichloromethane (100 mL). The solution was extracted three times with chloroform (50 ml) and the combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude oil was purified by method 2 to give 0.56 g (66%) of the title compound. 1 H NMR (400 MHz, CDCl 3): 9.97 (s, 1 H), 7.46-7.43 (m, 2 H), 7.39- 7.37 (m, 1 H), 7.19-7.15 (m, 1 H), 4.02 (t, J = 6.6 Hz, 2H), 2.86-2.80 (m, 2H), 2.25 (s, 3H), 1.92-1.83 (m, 2H), 1.83-1.75 (m, 2H), 1.73-1.63 (m, 2H), 1.54-1.44 (m, 2H), 1.34-1.18 (m, 5H).

C.6-Fluoro-7-methyl-2- (3-r4- (1-methyl-piperidin-4-n-butoxy-phenyl) -1H-benzoimidazole This compound was prepared by the method described in General procedure 3 using 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -benzaldehyde (20 mg, 0.07 mmol, 1.0 equiv.), 4-fluoro-3-methyl-benzene-1, 2 -diamine (12 mg, 0.09 mmol, 1.0 equiv.) and Na2S205 (18 mg, 0.10 mmol, 1.3 equiv.) Purification by method 2 gave 28.7 mg (54%) of the title compound. MS (electroaspersion): mass calculated for C24H3oFN30, 395.24, m / z found, 396.4 [M + H] +. 1H NMR (400 MHz, CD3OD): 7.72-7.62 (m, 2H), 7.47-7.32 (m, 2H), 7.08-6.94 (m, 2H), 4.07 (t, J = 6.3 Hz, 2H), 2.90-2.80 (m, 2H), 2.53 (s, 3H), 2.24 (s, 3H), 2.04-1.92 (m, 2H), 1.85-1.66 (m, 4H), 1.59-1.47 (m, 2H), 1.39-1.17 (m, 5H). The following compounds in Examples 96-101 were prepared according to the procedures described in Example 95.

EXAMPLE 96 7-Methyl-2-. { 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C 24 H 31 N 30, 377.25; m / z found, 378.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.86-7.71 (m, 2 H), 7.44 (br s, 1 H), 7.29-7.22 (m, 1 H), 7.26-7.09 (m, 1 H), 7.02 (d , J = 7.3 Hz, 1 H), 6.89 (dd, J = 8.2, 1.8 Hz, 1H), 3.59 (t, J = 6.4 Hz, 2H), 2.82 (m, 2H), 2.52 (br s, 3H) , 2.25 (s, 3H), 1.89 (m, 2H), 1.63-1.47 (m, 4H), 1.28-1.07 (m, 7H).

EXAMPLE 97 6, 7-Dimethyl-2-. { 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C25H33N30, 391.56; m / z found, 392.5 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.73-7.61 (m, 2H), 7.46-7.36 (m, 1 H), 7.36-7.25 (m, 1 H), 7.09-6.98 (m, 2H), 4.08 (t, J = 6.3 Hz, 2H), 2.93-2.82 (m, 2H), 2.53 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 2.08-1.97 (m, 2H), 1.86-1.68 (m, 4H), 1.60-1.47 (m, 2H), 1.39-1.17 (m, 5H).

EXAMPLE 98 -Chloro-7-methyl-2-. { 3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C24H30CIN3O, 411. twenty-one; m / z found, 412.4 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.73-7.62 (m, 2H), 7.47-7.38 (m, 2H), 7.09-7.02 (m, 2H), 4.09 (t, J = 6.3 Hz, 2H), 2.91-2.81 (m, 2H), 2.68 (s, 3H), 2. 24 (s, 3H), 2.05-1.93 (m, 2H), 1.87-1.67 (m, 4H), 1.60-1.48 (m, 2H), 1.39-1.18 (m, 5H).

EXAMPLE 99 ,7-Dimethyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H- benzoimidazole EM (electroaspersion): mass calculated for C26H35N30, 405.28; m / z found, 406.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.30-7.23 (m, 1 H), 7.19 (s, 1 H), 7.16-7.11 (m, 1 H), 7.07-7.01 (m, 1 H), 6.89 (s, 1 H ), 4.04 (t, J = 6.4 Hz, 2H), 2.89-2.80 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H) , 2.04-1.91 (m, 2H), 1.88-1.77 (m, 2H), 1.77-1.68 (m, 2H), 1.61-1.49 (m, 2H), 1.40-1.17 (m, 5H).

EXAMPLE 100 -Chloro-7-methyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C25H3 CIN30, 425.22; m / z found, 426.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 7.40 (s, 1 H), 7.33-7.24 (m, 1 H), 7.17-7.10 (m, 1 H), 7.10-7.02 (m, 2 H), 4.04 (t, J = 5.6 Hz, 2H), 2.91-2.80 (m, 2H), 2.56 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.04-1.92 (m, 2H), 1.89-1.65 (m, 4H), 1.63-1.48 (m, 2H), 1.41-1.16 (m, 5H).

EXAMPLE 101 6-Fluoro-7-methyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C25H32FN3O, 409.25; m / z found, 410.4 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.43-7.33 (s, 1 H), 7.30 (t, J = 7.8 Hz, 1H), 7.16-7.10 (s, 1 H), 7.10-6.96 (m, 2H), 4.05 (t, J = 5.4 Hz, 2H), 2.91-2.81 (m, 2H), 2.49 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 2.07-1.94 (m, 2H) , 1.89-1.67 (m, 4H), 1.63-1.49 (m, 2H), 1.41-1.16 (m, 5H).

EXAMPLE 102 6-Fluoro-7-methyl-2-. { 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy] -phenyl} -1H- benzoimidazole A.3-y3- (1-Methyl-piperidin-4-yloxy) -propoxyl-benzonitrile. To a mixture of 3- (1-methyl-piperidin-4-yloxy) -propan-1-ol (295 mg, 1.7 mmol, 1.0 equiv.) And triphenylphosphine supported on polymer (1.14 g, 3.41 mmol, 2.0 equiv.) in THF (40 ml) at 0 ° C, diisopropyl azodicarboxylate (0.67 ml, 3.41 mmol, 2.0 equiv.) was added dropwise by syringe. After 6 hr, the mixture was filtered through a glass frit and the filtrate was concentrated. The crude oil was purified by method 2 to give 187 mg (40%) of the title compound. MS (electroaspersion): mass calculated for C? 6H22N202, 274.17; m / z found, 275.4 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 7.40-7.33 (m, 1 H), 7.25-7.21 (m, 1 H), 7.17-7.10 (m, 2H), 4.09 (t, J = 6.2 Hz, 2H), 3.61 (t, J = 6.2 Hz, 2H), 3.34-3.25 (m, 1 H), 2.73-2.61 (m, 2H), 2.26 (s, 3H), 2.17-2.00 (m, 4H), 1.94-1.84 (m, 2H), 1.68-1.55 (m, 2H). B. 6-Fluoro-7-methyl-2- (3-f3- (1-methyl-piperidin-4-yloxy) -propoxp-phenyD-1 H-benzoimidazole. To a stirred solution of 3- [3- (1 methyl-piperidin-4-yloxy) -propoxy] -benzonitrile (0187 g, 0.68 mmol, 1.0 equiv.) in toluene (5.0 ml) at 0 ° C was added 1.5 M diisobutylaluminium hydride in toluene (1.02 ml, 1.02 mmol) 1.5 equiv.) After 3 hr, methanol (9 ml) and 1 M H2SO4 (10 ml) were added.The mixture was stirred for 30 min, then 1.0 M NaOH (10 ml) was added, followed by sodium tartrate. saturated aqueous sodium potassium (40 ml) and dichloromethane (100 ml) After stirring for 30 min, the mixture was extracted three times with chloroform (50 ml) and the combined extracts were washed with brine, dried (Na S04) were filtered and concentrated, The residue was partially purified by method 2 to give 106 mg of a mixture of 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy-benzaldehyde and some other non-purified products. identified A solution of 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy ] -benzaldehyde crude (53 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (27 mg) and Na2S2Os in DMF was stirred at 90 ° C for 18 h. The reaction mixture was loaded directly onto silica gel and purified according to method 2, which gave 28.7 mg of the title compound. EM (electroaspersion): mass calculated for C23H28FN302, 397.22; m / z found, 398.4 [M + H] +. 1 H NMR (400 MHz, CD3OD): 7.64-7.53 (m, 2H), 7.38-7.25 (m, 2H), 7.00-6.85 (m, 2H), 4.06 (t, J = 6.1Hz, 2H), 3.60- 3.52 (m, 2H), 3.33-3.19 (br s, 1 H), 2.58 (brs, 2 H), 2.42 (s, 3H), 2.17-2.03 (m, 5H), 2.01-1.90 (m, 2H) , 1.86-1.72 (m, 2H), 1.60-1.42 (m, 2H).

EXAMPLE 103 6-Chloro-4-methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1 H- benzoimidazole A.6-t3- (4-Methyl-Piperazin-1-yl) -propoxyl-nicotinonitrile. To a stirred solution of 3- (4-methyl-piperazin-1-yl) -propan-1-ol (1.0 g, 6.32 mmol, 1.0 equiv.) In DMF (60 mL) under a nitrogen atmosphere, hydride was added of sodium at 60% (379 mg, 9.48 mmol, 1.5 equiv.) in portions. Once the initial effervescence had ceased, the mixture was heated at 60 ° C for 1 hr, then cooled to room temperature. A solution of 6-chloronicotinonitrile (876 mg, 6.32 mmol, 1.0 equiv.) In DMF (5 mL) was then added and the mixture was stirred for 16 hr. The reaction mixture was partitioned between saturated aqueous NaHC03 (30 ml) and chloroform (60 ml). The organic layer was dried (Na S04), filtered and concentrated to give a crude mixture, which was purified by column chromatography (silica gel, 0-10% (2.0 M ammonia in methanol) in dichloromethane) to give 776 mg (47%) of a beige solid. MS (electroaspersion): mass calculated for C 14 H 20 N 4 O, 260.16; m / z found, 261.3 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 8.47 (dd, J = 2.3, 0.8 Hz, 1 H), 7.77 (dd, J = 8.6, 2.3 Hz, 1H), 6.80 (dd, J = 8.6, 0.8 Hz, 1 H), 4.41 (t, J = 6.6 Hz, 2H), 2.76-2.35 (m, 10H), 2.29 (s, 3H), 2.01-1.95 (m, 2H). B. 6- [3- (4-Methyl-piperazin-1-yl) -propoxyl-pyridino-3-carbaldehyde. To a cooled (0 ° C) solution of 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -nicotinonitrile (486 mg, 1.86 mmol, 1.0 equiv.) In toluene (20 ml), low a nitrogen atmosphere, 1M diisobutylaluminum hydride in hexanes (2.79 ml, 2.79 mmoles, 1.5 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hr. Methanol (5 ml) was added, followed by 1 M H2SO4 (10 ml). After stirring for 30 min, the solution was neutralized with saturated aqueous NaHCO3, diluted with saturated aqueous potassium sodium tartrate (10 mL), and stirred for an additional 30 minutes or until clear. The mixture was extracted with chloroform (3 x 50 ml) and the combined extracts were dried (Na 2 SO), and concentrated, giving the crude product, which was purified by column chromatography (silica gel, 0-10% (ammonia 2.0 M in methanol) in dichloromethane) to give 225 mg (46%) of a colorless residue.

MS (electroaspersion): mass calculated for C14H2I N3O2, 263.16; m / z found, 264.2 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 9.94 (1H, s), 8.61 (d, J = 2.3 Hz, 1 H), 8.06 (dd, J = 8.6, 2.3 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 4.46 (t, J = 6.6 Hz, 2H), 2.64-2.33 (m, 1.0 H), 2.29 (s, 3H), 2.03-1.96 (m, 2H). C. 6-Chloro-4-methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy-1-pyridin-3-yl} -1 H-benzoimidazole. This compound was prepared by the method described in general procedure 3 using 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridine-3-carbaldehyde (49 mg, 0.17 mmol, 1.0 equiv.) , 5-chloro-3-methyl-benzene-1,2-diamine (27 mg, 0.17 mmol, 1.0 equiv.) And Na2S205 (42 mg, 0.22 mmol, 1.3 equiv.). Purification by method 2 gave 54 mg (79%) of the title compound. MS (electroaspersion): mass calculated for C21H26CIN5O, 399.18; m / z found, 400.3 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 8.75 (s, 1 H), 8.25 (dd, J = 8.2, 2.4 Hz, 1 H), 7.49-7.32 (m, 1 H), 6.91 (s, 1 H), 6.71 (d, J = 8.7 Hz, 1H), 4.28 (t, J = 6.7 Hz, 2H), 2.67-2.31 ( m, 13H), 2.26 (s, 3H), 1.98-1.87 (m, 2H). The following compounds in Examples 104-105 were prepared according to the procedures described in Example 103.

EXAMPLE 104 4-Metii-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C21H27N5O, 365.47; m / z found, 366.2 [M + H] +.

EXAMPLE 105 -Fluoro-4-methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C21H26FN5O, 383.46; m / z found, 384.2 [M + H] +.

EXAMPLE 106 4-Methyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy-pyridin-3-yl} -1H-benzoimidazole A. 6-F3- (1-methyl-piperidin-4-yl) -propoxyl-nicotinonitrile. To a stirred solution of 3- (1-methyl-piperidin-4-yl) -propan-1-ol (5.0 g, 31.7 mmol, 1.1 equiv.) In DMF (200 ml) under a nitrogen atmosphere, 60% sodium hydride (1.73 g, 43.3 mmol, 1.5 equiv.) Was added in portions. Once the initial effervescence had ceased, the mixture was heated at 60 ° C for 1 hr, then cooled to room temperature. A solution of 6-chloronicotinonitrile (4.0 g, 28.9 mmol, 1.0 equiv.) In DMF (20 mL) was then added and the mixture was stirred for 16 hr. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). A precipitate was formed and collected by filtration under vacuum to give 3.67 g of the desired product. The filtrate was concentrated to half the volume and a second crop of precipitate was collected and combined to give 5.64 g (76%) of an orange solid, which was used without further purification. EM (electroaspersion): mass calculated for C15H21N3O, 259.17; m / z found, 260.4 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 8.46 (dd, J = 2.3, 0.8 Hz, 1 H), 7.77 (dd, J = 8.6, 2.3 Hz, 1 H), 6.80 (dd, J = 8.6, 0.8 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 2.96-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.68 (m, 7H), 1.37-1.34 (m, 2H), 0.89 -0.81 (m, 2H). B. 6-r 3 - (1-Met.l-piperidin-4-yl) -propoxp-pyridine-3-carbaldehyde. To a cooled (0 ° C) solution of 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -nicotinonitrile (640 mg, 2.47 mmol, 1.0 equiv.) In toluene (20 ml), under a nitrogen atmosphere, 1M diisobutylaluminum hydride in hexanes (3.70 ml, 3.70 mmol, 1.5 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hr. Methanol (5 ml) was added, followed by 1 M H2SO4 (10 ml). After stirring for 30 minutes, the solution was neutralized with saturated aqueous NaHCO3, diluted with saturated aqueous sodium potassium tartrate (10 ml), and stirred for an additional 30 minutes or until clear. The mixture was extracted with chloroform (3 x 50 ml) and the combined extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0-10% (2M ammonia in methanol) in dichloromethane) to give 598 mg (92%) of a colorless oil. MS (electroaspersion): mass calculated for C15H22N2O2, 262.17; m / z found, 263.1 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 9.87 (br s, 1 H), 8.53 (d, J = 2.3 Hz, 1 H), 7.98 (dd, J = 8.6, 2.3 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 4.34 (t, J = 6.6 Hz, 2H), 2.78-2.26 (m, 2H), 2.19 (s, 3H), 1.85-1.62 (m, 7H), 1.35-1.16 ( m, 4H). C. 4-Methyl-2- (6-r3- (1-methy [-piperidin-4-yl) -propoxp-pyridin-3-yl) -1 H -benzoimidazole. This compound was prepared by the method described in general procedure 3 using 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-carbaldehyde (100 mg, 0.38 mmol, 1.0 equiv. .), 3-methyl-benzene-1,2-diamine (46 mg, 0.38 mmol, 1.0 equiv.) And Na2S205 (94 mg, 0.50 mmol, 1.3 equiv.). Purification by method 2 gave 35 mg (25%) of the title compound.

MS (electroaspersion): mass calculated for C22H28N4O, 364.23; m / z found, 365.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.77 (s, 1 H), 8.23 (dd, J = 8.7.2.3 Hz, 1 H), 7.25 (m, 1 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.04-6.98 (m, 1H), 6.74 (d, J = 8.7 Hz, 1 H), 4.34 (t, J = 6.6 Hz, 2H), 2.84-2.76 (m, 2H), 2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.62 (m, 4H), 1.39-1.17 (m, 5H). The following compounds in Examples 107-108 were prepared according to the procedures described in Example 106.

EXAMPLE 107 4,5-Dimethyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H30N4O, 378.24; m / z found, 379.4 [M + H] +.

EXAMPLE 108 4-Chloro-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H-benzoimidazole EM (electroaspersion): mass calculated for C21H25CIN4O, 384.17; m / z found, 385.3 [M + H] +.

EXAMPLE 109 6-Chloro-4-methyl-2-. { 4-methyl-6- [3- (1-methyl-p -peridin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole A. 4-Methyl-6-3- (1-methyl-piperidin-4-yl) -propoxyl-nicotinonitrile. To a stirred solution of 2,2,6,6-tetramethyl-piperidine (0.20 mL, 1.16 mmol, 1.5 equiv.) In THF (3 mL) at -78 ° C was added 2.5 M n-butyllithium in hexanes ( 0.46 ml, 1.16 mmoles, 1.5 equiv.). After 10 min, the reaction mixture was heated at 0 ° C for 45 minutes before being cooled again to -78 ° C. A solution of 6- [3- (1-methy1-piperidin-4-yl) -propoxy] -nicotinonitrile (200 mg, 0.77 mmol, 1.0 equiv.) In THF (3 mL) was then added. After stirring for 1 hr at -78 ° C, the mixture was treated with methyl iodide (0.05 ml, 0.84 mmol, 1.1 equiv.) And the stirring was continued for 1.5 hr before being extinguished at -78 ° C with aqueous NaHCO 3. saturated (5 ml). The mixture was warmed to room temperature and extracted with chloroform (2 x 10 ml). The combined extracts were dried (Na 2 S 4), filtered and concentrated to give a crude residue, which was purified by method 2 to give 120 mg (57%) of the title compound. MS (electroaspersion): mass calculated for C 16 H 23 N 3 O, 273.18; m / z found, 274.4 [M + Hf. 1 H NMR (400 MHz, CDCl 3): 8.39 (s, 1 H), 6.67 (s, 1 H), 4.31 (t, J = 6.7 Hz, 2 H), 2.90-2.79 (m, 2 H), 2.48 (s, 3H), 2.28 (s, 3H), 1.95-1.63 (m, 6H), 1.40-1.20 (m, 5H). B.4-Methyl-6-f3-1-methyl-piperidin-4-yl) -propoxyl-pyridin-3-carbaldehyde. To a solution of 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -nicotinonitrile (260 mg, 0.95 mmol, 1.0 equiv.) In toluene (10 ml) at 0 ° C 1.5 M diisobutylaluminum hydride in toluene (1.26 ml, 1.90 mmol, 2. 0 equiv.). The mixture was warmed to room temperature and stirred for 2 hr. Methanol (2 ml) was added, followed by 1.0 M H2SO4 (3 ml). After stirring for 30 min, the solution was neutralized with saturated aqueous NaHCO3, diluted with saturated aqueous potassium sodium tartrate (10 mL), and stirred for an additional 30 minutes or until clear. The mixture was extracted with chloroform (3 x 15 ml) and the combined extracts were dried (Na2SO4), filtered and concentrated to give 200 mg of the crude product, which was used without purification. 1 H NMR (400 MHz, CDCl 3): 10.0 (s, 1 H), 8.47 (s, 1 H), 6.57 (s, 1 H), 4.35 (t, J = 6.7 Hz, 2H), 2.86-2.80 (m , 2H), 2.59 (s, 3H), 2.25 (s, 3H), 1.92-1.66 (m, 6H), 1.43-1.22 (m, 5H).

C. 4-Methyl-2-f6-r3- (1-methyl-piperidin-4-ip-propoxp-pyridin-3-ill-1 H-benzoimidazole) This compound was prepared by the method described in general procedure 3 using 4-Methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridine-3-carbaldehyde (60 mg, 0.22 mmol, 1.0 equiv.), 5-chloro-3-methyl-benzene -1, 2-diamine (34 mg, 0.22 mmol, 1.0 equiv.) And Na2S205 (54 mg, 0.29 mmol, 1.3 equiv.) Purification by method 2 gave 27 mg (30%) of the title compound. (electroaspersion): mass calculated for C23H2gCIN4 ?, 412.20, m / z found, 413.4 [M + H] +. 1H NMR (400 MHz, CD3OD): 8.77 (s, 1 H), 8.23 (dd, J = 8.7, 2.3 Hz, 1 H), 7.25 (m, 1 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.04-6.98 (m, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 4.34 (t, J = 6.6 Hz, 2H), 2.84-2.76 (m, 2H), 2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.62 (m, 4H), 1.39-1.17 (m, 4H). The following compounds in Examples 110-114 were prepared according to the procedures described in Example 109.

EXAMPLE 110 4-Methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H3oN40, 378.24; m / z found, 379.5 [M + H] +.

EXAMPLE 111 -Fluoro-4-methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H29FN4O, 396.23; m / z found, 397.4 [M + H] +.

EXAMPLE 112 4,5-Dimethyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.5 [M + H EXAMPLE 113 4,6-Dimethyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.5 [M + H] +.

EXAMPLE 114 4-Chloro-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-y!) - propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C22H27CIN4O, 398. 19; m / z found, 399.3 [M + H] +.

EXAMPLE 115 2-. { 4-Chloro-6- [3- (1-methyl-p -peridin-4-yl) -propoxy] -pyridin-3-yl} -5-fluoro-4-methyl-1H-benzoimidazole A. 4-Chloro-6-f3- (1-methy1-piperidin-4-yl) -propoxp-nicotinonitrile. To a stirred solution of 2,2,6,6-tetramethyl-piperidine (0.31 ml, 2.32 mmol, 1.2 equiv.) In THF (10 ml) at -78 ° C was added 1.6 M n-butyl lithium in hexanes (1.45 ml, 2.32 mmoles, 1.2 equiv.). After 10 minutes, the reaction mixture was heated at 0 ° C for 45 minutes before being cooled again to -78 ° C. Then a solution of 6- [3- (1-methyl-piperidin-4-yl) -propox '?] -nicotinonitrile (500 mg, 1.93 mmol, 1.0 equiv.) In THF (10 mL) was added. After being stirred for 1 hr at -78 ° C, the mixture was treated with hexachloroethane (0.05 ml, 0.84 mmol, 1.1 equiv.) In THF (2 ml) and allowed to warm to 0 ° C. Agitation was continued for 1.5 hr before becoming extinct 0 ° C with baking soda (10 ml). The mixture was warmed to room temperature and extracted with chloroform (2 x 20 mL). The combined extracts were dried (Na2SO), filtered and concentrated to give a crude residue, which was purified by method 2 to give 380 mg (67%) of the title compound. MS (electroaspersion): mass calculated for C15H20CIN3O, 293.13; m / z found, 294.5 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 8.43 (s, 1 H), 6.87 (s, 1 H), 4.35 (t, J = 6.7 Hz, 2 H), 2.97-2.88 (m, 2 H), 2.33 (s, 3H), 2.05-1.94 (m, 2H), 1.83-1.67 (m, 5H), 1.43-1.23 (m, 4H). B. 2- (4-Chloro-6-r3- (1-methyl-piperidin-4-yl) -propoxp-pyridin-3-yl) -5-fluoro-4-methyl-1 H-benzoimidazole . To a solution of 4-cORO-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -nicotinonitrile (380 mg, 1.30 mmol, 1.0 equiv.) In toluene (10 ml) at 0 ° C 1.5 M diisobutylaluminum hydride in toluene (1.72 ml, 2.60 mmol, 2.0 equiv.) was added. The mixture was warmed to room temperature and stirred for 2 hr. Methanol (5 ml) was added, followed by 1.0 M H2SO4 (5 ml). After stirring for 30 min, the solution was neutralized with saturated aqueous NaHCO3, diluted with saturated aqueous potassium sodium tartrate (10 mL), and stirred for an additional 30 minutes or until clear. The mixture was extracted with chloroform (3 x 15 ml) and the combined extracts were dried (Na2SO), filtered and concentrated to give 132 mg of the crude product which was used without purification. This crude mixture (33 mg, 0.11 mmol, 1.0 equiv.) Was used as described in general procedure 3 with 4-fluoro-3-methyl-benzene-1,2-diamine (16 mg, 0.11 mmol, 1.0 equiv. ) and Na2S205 (27 mg, 0.14 mmol, 1.3 equiv.). Purification by method 2 gave 12 mg (26%) of an oily residue. MS (electroaspersion): mass calculated for C22H26CIFN4O, 416.18; m / z found, 417.3 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.48 (s, 1 H), 7.41 (dd, J = 8.7, 4.3 Hz, 1 H), 7.46-6.99 (m, 2 H), 4.36 (t, J = 6.6 Hz, 2 H ), 2.91-2.82 (m, 2H), 2.50 (s, 3H), 2.25 (s, 3H), 2.06-1.95 (m, 2H), 1.88-1.69 (m, 4H), 1.47-1.18 (m, 5H) ). The following compounds in Examples 116-118 were prepared according to the procedures described in Example 115.

EXAMPLE 116 2-. { 4-Chloro-6- [3- (1-meth1l-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H27CIN4O, 398.19; m / z found, 399.3 [M + Hj +.

EXAMPLE 117 6-Chloro-2-. { 4-chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H26Cl2N40, 432.15; m / z found, 433.3 [M + H] 4 EXAMPLE 118 2-. { 4-Chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4,6-dimethyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN4O, 412. twenty; m / z found, 413.4 [M + H] +.

EXAMPLE 119 2-. { 4-Methoxy-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1H-benzoimidazole A solution of 4-chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -nicotinonitrile (example 115) in methanol (0.2 M) was treated with methoxide of sodium (4 equiv.) At reflux temperature for 4 hr. The mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3, and extracted with chloroform. The organic extract was dried (Na2SO4), filtered and concentrated to give 4-methoxy-6- [3- (1-meth1l-piperidin-4-yl) -propoxy] -nicotinonitrile (100%). This intermediate was converted to the title compound according to example 115. MS (electroaspersion): mass calculated for C23H30CIN4O2, 394.24; m / z found, 395.4 [M + H] +.

EXAMPLE 120 -Fluoro-2-. { 4-methoxy-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1 H-benzoimidazole The title compound was prepared according to the procedures described in Example 119. MS (electroaspersion): mass calculated for C23H29FN4O2, 412.23; m / z found, 413.4 [M + H] +.

EXAMPLE 121 -Fluoro-4-methyl-2-. { - [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1H-benzoimidazole A, 6-r3- (1-Methyl-1.2.3.6-tetrahydro-pyridin-4-i)) - propoxyl-nicotinonitrile. To a stirred solution of 3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propan-1-ol (1.23 g, 7.94 mmol, 1.1 equiv.) In DMF ( 50 ml), under a nitrogen atmosphere, 60% sodium hydride (433 mg, 10.8 mmol, 1.5 equiv.) Was added in portions. Once the initial effervescence had ceased, the mixture was heated at 60 ° C for 1 hr, then cooled to room temperature. A solution of 6-chloronicotinonitrile (1.0 g, 7.21 mmol, 1.0 equiv.) In DMF (5 mL) was then added and the mixture was stirred for 16 hr. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The mixture was extracted with chloroform (2 x 50 ml). The combined extracts were dried (Na2SO), filtered and concentrated to give a crude residue, which was purified by method 2 to give 1.43 g (77%) of the title compound. EM (electroaspersion): mass calculated for C? 5H? GN30, 257.15; m / z found, 258.3 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 8.46 (dd, J = 2.4, 0.6 Hz, 1 H), 7.76 (dd, J = 8.7.2.4 Hz, 1 H), 6.80 (dd, J = 8.7.0.6 Hz, 1 H), 5.44-5.39 (m, 1 H), 4.35 (t, J = 6.6 Hz, 2H), 2.92-2.87 (m, 2H), 2.51 (t, J = 5.8Hz, 2H), 2.34 (s) , 3H), 2.18-2.08 (m, 4H), 1.96-1.83 (m, 2H). B. 6-f3- (1 -Methyl-1, 2,3,6-tetrahvdro-pyridin-4-i0-propoxp-pyridine-3-carbaldehyde.) To a cooled solution (0 ° C) of 6- [ 3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -nicotinonitrile (1.42 mg, 5.56 mmol, 1.0 equiv.) In toluene (40 ml), under an atmosphere of nitrogen, 1.0 M diisobutylaluminum hydride in hexanes (8.34 ml, 8.34 mmol, 1.5 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 2 h. Methanol (5 ml) was added, followed by by H2SO4 1.0 M (10 mL) After stirring for 30 minutes, the solution was neutralized with saturated aqueous NaHC 3, diluted with saturated aqueous sodium potassium tartrate (25 mL), and stirred for an additional 30 minutes or The mixture was extracted with chloroform (3 x 50 ml) and the combined extracts were dried (Na 2 SO 4), filtered and concentrated to give 1.29 g of the product that was used without purification., CDCI3): 9.93 (s, 1 H), 8.60 (d, J = 2.3 Hz, 1 H), 8.05 (dd, J = 8.7.2.3 Hz, 1 H), 6.81 (d, J = 8.7 Hz, 1 H), 5.45-5.39 (m, 1 H), 4.40 (t, J = 6.6 Hz, 2H), 2.92-2.86 (m, 2H), 2.54-2.48 (m, 2H), 2.30 (s, 3H), 2. 8-2.09 (, 4H), 2.98-1.84 (m, 2H). C. 5-Fluoro-4-methyl-2- (6-r3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -proppyridin-3-yl.}. -1H-benzoimidazole This compound was prepared by the method described in general procedure 3 using 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] - pyridine-3-carbaldehyde (100 mg, 0.39 mmol, 1.0 equiv.), 4-fluoro-3-methyl-benzene-1,2-diamine (66 mg, 0.39 mmol, 1.0 equiv.) and Na2S205 (96 mg, 0.51) mmoles, 1.3 equiv.) Purification by method 2 gave 24 mg (16%) of the title compound MS (electroaspersion): mass calculated for C22H25FN4O, 380.20; m / z found, 381.4 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 11.8-10.8 (br s, 1 H), 8.86-8.58 (m, 1 H), 8.24 (dd, J = 8.7, 2.5 Hz, 1 H), 7.58-7.36 (m , 0.5H), 7.21-7.03 (m, 0.5H), 6.93 (t, J = 9.9 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 5.42-5.33 (m, 1H), 4.29 ( t, J = 6.7 Hz, 2H), 2.92-2.81 (m, 2H), 2.58-2.44 (m, 4H), 2.36-2.26 (m, 4H), 2.18-2.02 (m, 4H), 1.93-1.82 ( m, 2H). The following compounds in Examples 122-126 were prepared according to the procedures described in Example 121.

EXAMPLE 122 4-Methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C22H26N4O, 362.21; m / z found, 363.4 [M + H] +.

EXAMPLE 123 6-CIOR-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C22H25CIN4O, 396.17; m / z found, 397.4 [M + H] +.

EXAMPLE 124 4,5-DimetiI-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} - 1 H-benzoimidazole. MS (electroaspersion): mass calculated for C23H28N4O, 376.23; m / z found, 377.4 [M + H] +.

EXAMPLE 125 4,6-Dimethyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} - 1 H-benzoimidazole EM (electroaspersion): mass calculated for C23H28N4O, 376.23; m / z found, 377.4 [M + H] +.

EXAMPLE 126 -Chloro-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C22H25CIN4O, 396.17; m / z found, 397.4 [M + H] +.

EXAMPLE 127 -Fluoro-4-methyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -4-pyrroidin-1-ylmethyl-pyridin-3-yl} -1H-benzoimidazole A. 5-Bromo-2-y3- (1-methyl-piperidin-4-yl) -propoxy-1-pyridine. To a stirred solution of 3- (1-methyl-piperidin-4-yl) -propan-1-ol (2.0 g, 12.7 mmol, 1. 0 equiv.), In DMF (100 ml) under a nitrogen atmosphere, 60% sodium hydride (764 mg, 19.1 mmol, 1.5 equiv.) Was added in portions. Once the initial effervescence had ceased, the mixture was heated at 60 ° C for 1 hr, then cooled to room temperature. A solution of 2,5-dibromopyridine (3.0 g, 12.7 mmol, 1.0 equiv.) In DMF (7 mL) was then added and the mixture was stirred for 16 hr. The reaction was extinguished with Saturated aqueous NaHC03 (25 ml) and brine (25 ml). The mixture was extracted with chloroform (2 x 30 ml). The organic extracts were dried (Na2SO4), filtered and concentrated to give a crude residue, which was purified by the method 2 affording 3.31 g (88%) of the title compound. 1 H NMR (400 MHz, CDCl 3): 8.18-8.13 (m, 1 H), 7.65-7.58 (m, 1 H), 6.65-6.60 (m, 1 H), 4.21 (t, J = 6.7 Hz, 2H) , 2.87-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.62 (m, 6H), 1.43-1.17 (m, 5H).

B, 5-Bromo-2-y3- (1-methyl-piperidin-4-yl) -propoxp-pyridine-4-carbaldehyde. To a cooled solution (-78 ° C) of 2.0 M LDA in heptane / THF (4.05 ml, 8.07 mmol, 2.0 equiv.) In THF (20 ml), a solution of 5-bromo-2- was added dropwise. [3- (1-methyl-p -peridin-4-yl) -propoxy] -pyridine (1.2 g, 3.85 mmol, 1.0 equiv.) In THF (15 mL). After 30 min, DMF (1.49 mL, 19.2 mmol, 5.0 equiv.) Was added dropwise and the mixture was stirred for an additional 20 min at -78 ° C then warmed to 0 ° C and quenched with NaHCO 3. saturated aqueous (5 ml). The mixture was warmed to room temperature and extracted with chloroform (2 x 30 ml). The combined extracts were dried (Na 2 S 4), filtered and concentrated to give 1.10 g of a crude oil, which was used without purification. 1 H NMR (400 MHz, CDCl 3): 10.3 (s, 1 H), 8.39 (s, 1 H), 7.15 (s, 1 H), 4.31 (t, J = 6.7 Hz, 2 H), 2.87-2.75 (m, 2H), 2.28 (s, 3H), 1.97-1.60 (m, 6H), 1.43-1.15 (m, 5H). C. 5-Bromo-2- 3- (1-methyl-piperidin-4-yl) -propoxp-4-pyrrolidin-1-ylmethyl-pyridine. To a mixture of 5-bromo-2- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridine-4-carbaldehyde (85 mg, 0.25 mmol, 1.0 equiv.) And pyrrolidine (0.05 ml, 0.62 mmol, 2.5 equiv.) In dichloroethane (5 ml), sodium triacetoxyborohydride (156 mg, 0.74 mmol, 3.0 equiv.) Was added. After 24 hr, the mixture was neutralized with saturated aqueous NaHCO 3 and extracted with chloroform (2 x 15 ml). The combined extracts were dried (Na2SO4), filtered and concentrated to give a crude oil product, which was purified by method 2 to give 38 mg of a white solid. 1 H NMR (400 MHz, CDCl 3): 8.15 (s, 1 H), 6.90 (s, 1 H), 4.24 (t, J = 6.7 Hz, 2 H), 3.65 (s, 2 H), 2.87-2.77 (m, 2H), 2.64-2.53 (m, 4H), 2.25 (s, 3H), 1.95-1.62 (m, 10H), 1.42-1.20 (m, 5H). jD. 5-Fluoro-4-methyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -4-pyrrolidin-1-ylmethyl-pyridin-3-yl} -1 H-benzoimidazole. To a cooled solution (-78 ° C) of 5-bromo-2- [3- (1-methyl-piperidin-4-yl) -propoxy] -4-pyrrolidin-1-ylmethyl-pyridine (38 mg , 0.10 mmol, 1.0 equiv.) In dry THF (2 mL), under a nitrogen atmosphere, n-butyllithium (2.75 M in hexanes, 0.04 mL, 0.11 mmol, 1.1 equiv.) Was added dropwise. After 10 min, DMF (0.07 ml, 1.00 mmol, 10.0 equiv.) Was added. The solution was warmed to 0 ° C, quenched with saturated aqueous NaHCO3 (2 mL), and extracted with chloroform (2 x 10 mL). The combined extracts were dried (Na2SO4), filtered and concentrated to obtain a crude residue. This residue was immediately dissolved in DMF (2 ml) and treated with 4-fluoro-4-fluoro-3-methyl-benzene-1,2-diamine (15 mg, 0.11 mmol, 1.1 equiv.) And Na2S205 (25 mg. , 0.13 mmol, 1.3 equiv.) In accordance with general procedure 3. Purification by method 2 gave 10 mg (22%) of the title compound. EM (electroaspersion): mass calculated for C27H36FN5O, 465.26; m / z found, 466.5 [M + H] +. 1 H NMR (400 MHz, CD3OD): 8.81 (s, 1 H), 7.42 (dd, J = 8.7, 4.3 Hz, 1 H), 7.01 (dd, J = 10.3, 8.8 Hz, 1H), 6.95 (s, 1H), 4.40 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 2.94-2.81 ( m, 2H), 2.77-2.66 (m, 4H), 2.51 (s, 3H), 2.25 (s, 3H), 2.00-1.92 (m, 6H), 1.89-1.70 (m, 4H), 1.46-1.19 ( m, 5H).

EXAMPLE 128 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-methyl-1H-benzoimidazole. A. 5-Bromo-2-y4- (1-methyl-piperidin-4-ip-butoxp-pyridine) To a stirred solution of 4- (1-methyl-piperidin-4-yl) -butan-1 -ol (3.98 g, 623 mmol, 1.1 equiv.) in DMF (100 ml), under a nitrogen atmosphere, was added in portions 60% sodium hydride (1.26 mg, 6.81 mmol, 1.5 equiv.). When the initial effervescence had ceased, the mixture was heated at 60 ° C for 1 hr, then cooled to room temperature A solution of 2,5-dibromopyridine (5 mg, 21.1 mmol, 1.0 equiv.) in DMF (50 ml. ) was then added and the mixture was stirred for 16 hr.The mixture was divided between Saturated aqueous NaHC03 (100 ml) and chloroform (200 ml). The chloroform layer was dried (Na2SO), filtered and concentrated to give a crude mixture, which was purified by column chromatography (silica gel, 0-10% (2 M ammonia in methanol) in dichloromethane) to give 2.73 g (40%) of a white solid. MS (electroaspersion): mass calculated for C 5H23BrN20, 326.1; m / z found, 327.3 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 8.17 (d, J = 2.5 Hz, 1 H), 7.63 (dd, J = 7.6, 2.5 Hz, 1 H), 6.63 (d, J = 8.8 Hz, 1 H), 4.24 (t, J = 6.6 Hz, 2H), 2.91-2.80 (m, 2H), 2.27 (s, 3H), 1.98-1.88 (m, 2H), 1.79-1.63 (m, 4H), 1.49-1.38 ( m, 2H), 1.34-1.20 (m, 5H). B. 5-Bromo-2-y4- (1-methyl-piperidin-4-ip-butoxy-1-pyridine-4-carbaldehyde) To a cooled solution (-78 ° C) of 2.0 M LDA in heptane / THF (3.47 ml) , 6.94 mmol, 2.0 equiv.) In THF (10 mL), was added dropwise a solution of 5-bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine (1.13 g, 3.47 mmol, 1.0 equiv.) in THF (15 ml) After 30 min, DMF (1.07 ml, 13.9 mmol, 4.0 equiv.) was added dropwise and the mixture was stirred for an additional 20 minutes at -78. C. The mixture was warmed to 0 ° C and saturated aqueous NaHCO3 (5 ml) was added.After warming to room temperature, the mixture was extracted with chloroform (2 x 20 ml) .The combined extracts were dried (Na2S0). , filtered and concentrated to give 1.34 g of a crude orange oil which was used without purification.1H NMR (400 MHz, CDCl3): 10.3 (s, 1 H), 8.39 (s, 1 H), 7.14 (s, 1 H), 4.31 (t, J = 6.7 Hz, 2H), 2.89-2.79 (m, 2H), 2.28 (s, 3H), 1.96-1.63 (m, 9H), 1.43-1.20 (m, 4H). C. 2- (5-Bromo-2-f4- (1-methyl-piperidin-4-yl) -butoxy-pyridin-4-yl-4-methyl-1 H-benzoimidazole This compound was prepared by the method described in general procedure 3 using 5-bromo-2- [4- (1-methy1-piperidin-4-yl) -butoxy] -pyridine-4-carbaldehyde (100 mg, 0.28 mmol, 1.0 equiv. ), 3-methyl-benzene-1,2-diamine (38 mg, 0.31 mmol, 1.1 equiv.) And Na2S205 (70 mg, 0.37 mmol, 1.3 equiv.) Purification by method 2 gave 25 mg (20%) ) of the title compound: MS (electroaspersion): mass calculated for C23H29BrN40, 456.15, m / z found, 466.5 [M + H] +. 1 H NMR (400 MHz, CDCl 3): 10.6-10.3 (brs, 1 H), 8.45-8.28 (m, 1H), 7.76-7.62 (m, 2H), 7.25-7.21 (m, 1 H), 7.19-7.07 (m, 1H), 4.29 (t, J = 6.7 Hz, 2H), 2.87 -2.77 (m, 2H), 2.76-2.63 (m, 3H), 2.25 (s, 3H), 1.95-1.61 (m, 7H), 1.53-1.39 (m, 2H), 1.35-1.15 (m, 4H) The following compounds in Examples 129-135 were prepared according to the procedures described in Example 128.

EXAMPLE 129 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-fluoro-4-methyl-1H-benzoimidazoi MS (electroaspersion): mass calculated for C23H28BrFN50, 474.14; m / z found, 477.4 [M + H] +.

EXAMPLE 130 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -6-chloro-4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H28BrCIN50, 490.1; m / z found, 493.4 [M + H] +.

EXAMPLE 131 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,6-dimethyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C 24 H 3iBr N 0, 470.17; m / z found, 471.4 [M + Hf.

EXAMPLE 132 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C24H3iBrN40, 470.17; m / z found, 471.4 [M + Hf.

EXAMPLE 133 2-. { 5-Bromo-2- [4- (1-methyl-p-pperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C24H3iBrN4 ?, 470. 17; m / z found, 471.4 [M + H] +. EM (electroaspersion): mass calculated for C23H28BrCIN4 ?, 490. eleven; m / z found, 493.4 [M + H] +.

EXAMPLE 134 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-tert-butyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C26H35BrN 0.498.20; m / z found.501.4 [M + H] +.

EXAMPLE 135 -fer-Butl-2-. { 2- [4- (1-methy) -p-perldn-4-yl) -butoxy] -pyridin-4-yl} -1H-benzoimidazole EM (electroaspersion): mass calculated for C 26 H 36 N 4 O, 420.29; m / z found, 421.5 [M + H] +.

EXAMPLE 136 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-fluoro-4-methy1-1H-benzoimidazole A. 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxyfl-pyridine. To a stirred solution of 4- (1-methyl-piperidin-4-yl) -butan-1-ol (1.5 g, 8.77 mmol, 1.0 equiv.) In DMF (10 mL) under a nitrogen atmosphere, was added in 60% sodium hydride portions (573 mg, 14.3 mmol, 1.5 equiv.). Once the initial effervescence had ceased, the mixture was heated at 60 ° C for 1 hr, then cooled to room temperature. A solution of 2,5-dichloropyridine (1.42 mg, 9.55 mmol, 1.1 equiv.) In DMF (10 mL) was then added and the mixture was stirred for 4 hr. The mixture was partitioned between saturated aqueous NaHC 3 (20 ml) and chloroform (40 ml). The chloroform layer dried (Na 2 S 4), filtered and concentrated to give a crude mixture, which was purified by column chromatography (silica gel, 0-10% (2 M ammonia in methanol) in dichloromethane) to give 1.62 g (65%) ) of a white solid. 1 H NMR (400 MHz, CDCl 3): 8.07 (dd, J = 2.5, 0.4 Hz, 1 H), 7.51 (dd, J = 8.8, 2.7 Hz, 1H), 6.67 (dd, J = 8.8.0.4 Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 2. 86-2.78 (m, 2H), 2.26 (s, 3H), 1.94-1.60 (m, 7H), 1.52-1.37 (m, 2H), 1.35-1.14 (m, 4H).

B, 5-Chloro-2-f4- (1-methyl-pperidin-4-yO-butoxy-pyridine-4-carbaldehyde.) To a cooled solution (-78 ° C) of 2.0 M LDA in heptane / THF (5.74 mL, 11.5 mmol, 2.0 equiv.) in THF (10 mL), a solution of 5-chloro-2- [4- (1-methyl-piperidin-4-yl) - was added dropwise butoxy] -pyridine (1.62 g, 5.74 mmol, 1.0 equiv.) in THF (15 ml) After 30 min, DMF (2.22 ml, 28.7 mmol, 5.0 equiv.) was added dropwise and the mixture was stirred for An additional 20 minutes at -78 ° C. The mixture was warmed to 0 ° C. and quenched with saturated aqueous NaHCO 3 (5 ml) The mixture was warmed to room temperature and extracted with chloroform (2 x 20 ml). The combined extracts were dried (Na2SO4), filtered and concentrated to give 968 mg of a crude residue, which was used without purification, 1 H NMR (400 MHz, CDCl 3): 10.4 (s, 1 H), 8.26 (s, 1 H). ), 7.13 (s, 1 H), 4.31 (t, J = 6.6 Hz, 2H), 2.87-2.80 (m, 2H), 2.25 (s, 3H), 1.99-1.60 (m, 7H), 1.51-1.38 (m, 2H), 1.43-1.20 (m, 4H), C. 2- {5-Chloro-2-y4 - (1-methyl-piperidin-4-yl) -butoxyl-pyridin-4-yl-5-fluoro-4-methyl-1 H-benzoimidazole. This compound was prepared by the method described in general procedure 3 using 5-chloro-2- [4- (1-methyl-piperidin-4-ii) -butoxy] -pyridine-4-carbaldehyde (45 mg, 0.15 mmol, 1.0 equiv.), 4-fluoro-3-methyl-benzene-1,2-diamine (23 mg, 0.17 mmol, 1.1 equiv.) And Na2S20s (37 mg, 0.20 mmol, 1.3 equiv.). Purification by method 2 gave 12 mg (18%) of the title compound. MS (electroaspersion): mass calculated for C23H28CIFN4O, 430.19; m / z found, 431.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.30 (s, 1 H), 7.45 (dd, J = 8.9, 4.5 Hz, 1 H), 7.22-7.10 (m, 1 H), 7.07 (dd, J = 10.2, 8.9 Hz 1 H), 4.31 (t, J = 6.6 Hz, 2H), 2.88-2.81 (m, 2H), 2.53 (s, 3H), 2.24 (s, 3H), 2.05-1.90 (m, 2H), 1.84 -1.66 (m, 4H), 1.55-1.42 (m, 2H), 1.37-1.15 (m, 5H).

EXAMPLE 137 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-ii) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1H-benzoimidazole The title compound was prepared according to the methods described in Example 36. MS (electroaspersion): mass calculated for C 24 H 3iClN 40, 426.22; m / z found, 427.4 [M + H] +.

EXAMPLE 138 4,6-Dimethyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1H-benzoimidazole A. 2-γ4- (4-Methyl-piperazin-1-yl) -butoxy-1-isonicotinonitrile. To a solution of 4- (4-methyl-piperazin-1-yl) -butan-1-ol (2.5 g, 14.5 mmol, 1.0 equiv.) In DMF (25 mL) at 0 ° C was added Sodium hydride (60% dispersion in oil, 0.70 g, 17.4 mmol, 1.2 equiv.). The mixture was warmed to room temperature and stirred for 1 hr before being cooled back to 0 ° C. A solution of 2-chloro-isonicotinonitrile (2.01 g, 14.5 mmol, 1.0 equiv.) In DMF (12 mL) was added dropwise. The mixture was stirred at room temperature for 18 h. The reaction was diluted with water (5 ml) and saturated aqueous NaHCO3 (25 ml) was added. The mixture was extracted with chloroform (3 x 25 mL), and the combined extracts were concentrated. Purification by method 2 gave 1.07 g of impure compound. Mass calculated for C? 5H22N40, 274.18; m / z found, 275.4 [M + H] +. B. 4.6-Dimethyl-2-. { 2-r4- (4-methyl-piperazin-1-yl) -butoxy-pyridin-4-yl > - 1 H-benzoimidazole. To a stirred solution of 2- [4- (4-methyI-piperazin-1-yl) -butoxy-isonicotinonitrile) in toluene (5.0 ml) at 0 ° C was added 1.5 M diisobutylaluminium hydride in toluene (3.9 ml, 5.86 g. mmoles, 1.5 equiv.). After 3 hr, methanol (9 ml) and H S04 1.0 M (10 ml) were added. The mixture was stirred for 30 min, and then 1.0 M NaOH (10 mL) was added, followed by saturated aqueous sodium potassium tartrate (40 mL) and dichloromethane (100 mL). After being stirred for 30 min, the mixture was extracted with chloroform (3 x 50 ml) and the combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was partially purified by method 2 to give 240 mg of a mixture of 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy] -benzaldehyde and some other unidentified products. A portion of the crude product 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy] -benzaldehyde (40 mg), 3,5-dimethyl-benzene-1,2-diamine (17.6 mg), and Na2S205 (32 mg) was stirred in DMF (4 mL) at 90 ° C for 18 hr. The reaction mixture was loaded directly onto silica gel and purified by method 2, which gave 1-9 mg of the title compound. EM (electroaspersion): mass calculated for C23H3? N50, 393.25; m / z found, 394.5 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.26 (d, J = 5.4 Hz, 1 H), 7.63 (d, J = 5.5 Hz, 1 H), 7.49 (s, 1 H), 7.25 (br s, 1 H), 6.95 (s, 1H), 4.38 (t, J = 6.3 Hz, 2H), 2.76-2.33 (m, 16H), 2.32-2.24 (s, 3H), 1.92-1.79 (m, 2H), 1.79-1.66 (m , 2H). The following compounds in Examples 139-142 were prepared according to the procedures described in Example 138.

EXAMPLE 139 4-Methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C22H29N5O, 379.24; m / z found, 380.4 [M + H] +.

EXAMPLE 140 4,5-Dimethyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C23H3? N50, 393.25; m / z found, 394.5 [M + H] +.

EXAMPLE 141 -Fluoro-4-methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-i !} -1H- benzoimidazole EM (electroaspersion): mass calculated for C22H28FN5O, 397.23; m / z found, 398.4 [M + Hf.

EXAMPLE 142 6-Chloro-4-metii-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C22H28CIN50, 413.20; m / z found, 414.4 [M + H] +.

EXAMPLE 143 -Fluoro-4-methyl-2-. { 2- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole A. 2-r4- (4-Methyl-1,4ldiazepan-1-ip-butoxp-isonicotinonitrile) To a solution of 1-methyl- [1,4] diazepam (21.3 g, 185 mmol, 2.0 equiv.) and 4-chloro-butan-1-ol (10.0 g, 92.6 mmol, 1.0 equiv.) in 1-butanol (200 ml) were added K2CO3 (38.0 g, 278 mmol, 3.0 equiv.) and Nal (13.9 g. g, 92.6 mmol, 1.0 equiv.) The mixture was heated to 95 ° C and stirred for 36 hr.The mixture was then cooled to room temperature, diluted with water, and extracted with chloroform (3 x 100 ml). The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated. Purification by method 2 gave 9.3 g of 4- (4-methyl- [1,4] diazepan-1-yl) -butanol with a small unidentified impurity. A portion of the doped alcohol (5.0 g) was dissolved in DMF (50 ml) and cooled to 0 ° C. Sodium hydride (60% dispersion in oil, 1.29 g, 32.2 mmol, 1.2 equiv.) Was added. The mixture was warmed to room temperature, stirred for 1 hr, and then cooled again to 0 ° C. A solution of 2-chloro-isonicotinonitrile (3.72 g, 26.8 mmol, 1.0 equiv.) In DMF (25 mL) was added dropwise. The mixture was stirred at room temperature for 18 hr, then diluted with water (25 ml) and saturated aqueous NaHCO 3 (100 ml), and extracted with chloroform (3 x 100 ml). The combined extracts were washed with brine, dried (Na 2 SO 4), filtered and concentrated. Purification by method 2 gave the title compound (1.0 g). EM (electroaspersion): mass calculated for C16H24N4O, 288.20; m / z found, 289.4 [M + Hf. 1 H NMR (400 MHz, CDCl 3): 8.28 (dd, J = 4.4 Hz, 0.8 Hz, 1 H), 7.05 (dd, J = 3.9.1.1 Hz, 1 H) 6.96 (s, 1 H), 4.33 (t , J = 6.6 Hz, 2H), 2.75-2.68 (m, 4H), 2.65-2.57 (m, 4H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.84-1.74 (m, 4H) ), 1.66-1.55 (m, 2H). B. 5-Fluoro-4-methyl-2- (2-γ4- (4-methyl-p, 41-diazepane-1-yl) -butoxy-pyridin-4-yl-1H-benzoimidazole. To a stirred solution of 2 - [4- (4-methyl- [1, 4] diazepan-1-yl) -butoxy] -sonicotinonitrile (1.0 g, 3.47 mmol, 1.0 equiv.) In toluene (5.0 mL) at 0 ° C was added hydride 1.0 M diisobutylaluminum in toluene (5.2 ml, 5.2 mmol, 1.5 equiv.) After 3 h, methanol (9 ml) and 1.0 M H2SO4 (10 ml) were added.The mixture was stirred for 30 min, and then added 1.0 M NaOH (10 mL), followed by saturated aqueous sodium potassium tartrate (40 mL) and dichloromethane (100 mL) After stirring for 30 minutes, the mixture was extracted with chloroform (3 x 50 mL) and the The combined extracts were washed with brine, dried (Na 2 SO 4), filtered and concentrated The residue was partially purified by method 2 to give 268 mg of a mixture of 2- [4- (4-methyl- [1 , 4] diazepan-1-yl) -butoxy] -pyridine-4-carbaldehyde and some other unidentified products A portion of 2- [4- (4-me 1- (4,4-D-azepan-1-yl) -butoxy] -pyridine-4-carbaldehyde doped (63 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (30.3 mg), and Na2S20d (53.4 mg) were stirred in DMF (3 ml) at 90 ° C for 18 hr. The reaction mixture was loaded directly onto silica gel and purified by method 2, which gave 5.0 mg of the title compound. MS (electroaspersion): mass calculated for C23H3oFN50, 411.24; m / z found, 412.5 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 8.27 (dd, J = 4.8, 0.5 Hz, 1 H), 7.63 (d, J = 4.0, 1.4 Hz, 1 H), 7.52-7.40 (m, 2 H), 7.10- 7.01 (m, 1H), 4.27 (t, J = 6.3 Hz, 2H), 2.86-2.77 (m, 4H), 2.77-2.68 (m, 4H), 2.65-2.57 (m, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.90-1.66 (m, 6H).

EXAMPLE 144 4,5-Dimethyl-2-. { 2- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole This compound was prepared according to the methods described in Example 143. MS (electroaspersion): mass calculated for C2 H35N50, 407.27; m / z found, 408.5 [M + H] +.

EXAMPLE 145 4,6-Dimeti-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole A. 2- [4- (1-Methyl-piperidin-4-yl) -butoxy] -isonicotinonitrile. To a solution of 4- (1-methyl-piperidin-4-yl) -butan-1-ol (1.0 g, 5.85 mmol, 1.0 equiv.) In DMF (25 mL) at 0 ° C was added sodium hydride ( 60% dispersion in oil, 0.28 g, 7.02 mmol, 1.2 equiv.). The mixture was warmed to room temperature and stirred for 1 hr. The mixture was then re-cooled to 0 ° C and a solution of 2-chloro-isonicotinonitrile (0.81 g, 5.85 mmol, 1.0 equiv.) In DMF (10 ml) was added dropwise. The mixture was stirred at room temperature for 18 hr, then diluted with water (25 ml) and saturated aqueous NaHCO 3 (100 ml). The mixture was extracted with chloroform (3 x 100 ml), and the combined extracts were concentrated. Purification by method 2 gave 0.44 g (28%) of the title compound. MS (electroaspersion): mass calculated for C? 6H23N30, 273.18; m / z found, 274.4 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 8.28 (dd, J = 5.2, 0.7 Hz, 1H), 7.05 (dd, J = 5.2, 1.3 Hz, 1 H), 6.99-6.95 (m, 1 H), 4.21 ( t, J = 6.6 Hz, 2H), 2.88-2.79 (m, 2H), 2.26 (s, 3H), 1.95-1.83 (m, 2H), 1.81-1.59 (m, 4H), 1.51-1.38 (m, 2H), 1.34-1.16 (m, 5H). B.4,6-Dimethyl-2-. { 2-r4-1-methyl-piperidin-4-yl) -butoxy-pyridin-4-yl > -1H-benzoimidazole. To a stirred solution of 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -isonicotinonitrile (440 mg, 1.61 mmol, 1.0 equiv.) In toluene (5.0 mL) at 0 ° C was added hydride 1.0 M diisobutylaluminum in toluene (2.41 ml, 2.41 mmoles, 1.5 equiv.). After 3 h, methanol (8 ml) and H2SO4 (5 ml) 1.0 M were added. The mixture was stirred for 30 min, and then 1.0 M NaOH (10 ml) was added, followed by saturated aqueous sodium potassium tartrate. (40 ml) and dichloromethane (100 ml). After being stirred for 30 min, the mixture was extracted with chloroform (3 x 50 ml) and the combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was partially purified by method 2 to give 318 mg of a mixture of 2- (4-piperidin-4-yl-butoxy) -pyridine-4-carbaldehyde and some other unidentified products. A portion of crude 2- (4-piperidin-4-yl-butoxy) -pyridine-4-carbaldehyde (100 mg), 3,5-dimethyl-benzene-1,2-diamine (70 mg), and Na2S20s (93 mg) were stirred in DMF (3 ml) at 90 ° C for 18 hr. The reaction mixture was loaded directly onto silica gel and purified according to method 2, which gave 38 mg of the title compound. MS (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found 393.4 [M + H] +. 1 H NMR (400 MHz, CD 3 OD): 8.25 (d, J = 5.3 Hz, 1 H), 7.62 (dd, J = 4.5, 1.0 Hz, 1 H), 7.48 (s, 1 H), 7.24 (s, 1 H), 6.95 (s, 1H), 4.34 (t, J = 6.6 Hz, 2H), 2.91-2.83 '(m, 2H), 2.58 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H), 2.07-1.95 (m, 2H), 1.86-1.69 (m, 5H), 1.57-1.18 (m, 6H). The following compounds in Examples 146-151 were prepared according to the methods described in Example 145.

EXAMPLE 146 4-Methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole EM (electroaspersion): mass calculated for C23H30N4O, 378.24; m / z found, 379.4 [M + H] +.

EXAMPLE 147 -Fluoro-4-methyl-2-. { 2- [4- (1-methy1-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H29FN4O, 396.23; m / z found, 387.4 [M + H] +.

EXAMPLE 148 4-Chloro-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H-benzoimidazole MS (electroaspersion): mass calculated for C22H27CIN4O, 398.19; m / z found, 398.4 [M + H] + - EXAMPLE 149 4,5-Dimethyl-2-. { 2- [4- (1-methyl-piperid-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole MS (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.5 [M + Hf.

EXAMPLE 150 6-Chloro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H29CIN4O, 412.20 m / z found; 413.4 [M + Hf.

EXAMPLE 151 -Chloro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H2gCIN4 ?, 412.24; m / z found, 413.4 [M + Hf.

EXAMPLE 152 -tert-Butyl-2- [2- (4-piperidin-4-yl-butoxy) -pyridin-4-yl] -1 H -benzoimidazole The title compound was prepared according to the methods described in Example 145 , using 4- (4-hydroxy-butyl) -piperidine-1-carboxylic acid tert-butyl ester in place of 4- (1-methyl-piperidin-4-yl) -butan-1-ol to give ter- butyl acid 4-. { 4- [4- (5-tert-butyl-1 H-benzoimidazol-2-yl) -pyridin-2-yloxy] -butyl ester} -piperidin-1 -carboxylic acid. This intermediate was then converted to the title compound as described in example 14.

EM (electroaspersion): mass calculated for C25H34N40, 406.27; m / z found, 407.5 [M + Hf.

EXAMPLE 153 4,6-Dimethyl-2- [2- (4-piperidin-4-yl-butoxy) -pyridin-4-yl] -1 H -benzoimidazole The title compound was prepared according to the procedures as described in example 152. MS (electroaspersion): mass calculated for C23H30N4O, 378.24; m / z found, 379.5 [M + Hf.

EXAMPLE 154 2-. { 2- [4- (1-Ethyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-DimetiI-1 H-benzoimidazole The title compound was prepared according to the methods described in Example 90. MS (electroaspersion): mass calculated for C25H34N4O, 406.27; m / z found, 407.4 [M + Hf.

EXAMPLE 155 4,6-Dimethyl-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole A. 3-Methyl-2- [4- (1-methyl-p -peridin-4-yl) -butoxy-1-isonicotinonitrile. To a flask dried in an oven under N2 was added 2,2,6,6-tetramethylpiperidine (2.13 ml, 12.6 mmol 1.5 equiv.) And THF (50 ml). The flask was cooled to -78 ° C and n-butyllithium (2.5 M in hexanes, 5.03 ml, 12.6 mmol, 1.5 equiv.) Was added. The mixture was heated at 0 ° C for 1 hr, and then cooled again to -78 ° C. A solution of 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -isonicotinonitrile (2.3 g, 8.38 mmol, 1.0 equiv.) In THF (15 mL) was added dropwise and the mixture The resulting mixture was stirred at -78 ° C for 1 hr. Methyl iodide (1.30 g, 9.22 mmol, 1.1 equiv.) In THF (10 mL) was added dropwise. After 1 hr, the reaction was quenched with saturated aqueous NaHCO 3, warmed to room temperature, diluted with chloroform and washed with saturated aqueous NaHCO 3. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by method 2 gave 405 mg of a mixture of 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -isonicotinonitrile and other unidentified products.

MS (electroaspersion): mass calculated for C17H25N3O, 287.20; m / z found, 288.4 [M + Hf. B. 4.6-Dimethyl-2-. { 3-methyl-2-r4- (1-methyl-piperidin-4-yl) -butoxy-pyridin-4-yl} -1 H-benzoimidazole. To a stirred solution of doped 3-metiI-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -isonicotinonitrile (283 mg) at 0 ° C was added 1.5 M diisobutylaluminium hydride in toluene (1.32). ml). After 3 hr, methanol (8 ml) and 1.0 M H2SO4 (5 ml) were added. The mixture was stirred for 30 min, then 1.0 M NaOH (10 ml) was added, followed by saturated aqueous sodium potassium tartrate (40 ml) and dichloromethane (100 ml). After stirring for 30 minutes, the mixture was extracted with chloroform (3 x 50 ml) and the combined extracts were washed with brine, dried (Na 2 SO 4), filtered and concentrated. The residue was partially purified by method 2 to give 180 mg of a mixture of 2- (4-piperidn-4-yl-butoxy) -pyridine-4-carbaldehyde and some other unidentified products. A portion of the doped 2- (4-piperidin-4-yl-butoxy) -pyridine-4-carbaldehyde (19.5 mg), 3,5-dimethyl-benzene-1,2-diamine (9.2 mg) and Na2S205 (16.6 mg) were stirred in DMF (3 ml) at 90 ° C for 18 hr. The reaction mixture was loaded directly onto silica gel and purified by method 2, which gave 9.4 mg of the title compound. EM (electroaspersion): mass calculated for C25H34N4O, 406.27; m / z found, 407.5 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 8.06 (dd, J = 5.3.0.4 Hz, 1 H), 7.23 (s, 1 H), 7.13 (d, J = 5.3 Hz, 1 H), 6.94 (s, 1 H) , 4.36 (t, J = 6.4 Hz, 2H), 2.92- 2.81 (m, 2H), 2.56 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.07-1.94 (m, 2H), 1.87-1.67 (m, 4H), 1.60-1.46 (m, 2H), 1.40-1.15 (m, 5H). The following compounds in Examples 156-157 were prepared according to the procedures described for Example 155.

EXAMPLE 156 4-Methyl-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 32 N 4 O, 392.26; m / z found, 393.4 [M + Hf.

EXAMPLE 157 6-Chloro-4-metii-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 31 CIN 4 O, 426.22; m / z found, 427.4 [M + Hf.

EXAMPLE 158 2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-methyl-1 H-benzoimidazole The title compound was prepared as described in Example 155, using hexachloroethane in place of methyl iodide. EM (electroaspersion): mass calculated for C23H29CIN4O, 412. twenty; m / z found, 413.4 [M + Hf. The following compounds in Examples 159-164 were prepared according to the procedures described in Example 158.

EXAMPLE 159 2-3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1 H- benzoimidazole EM (electroaspersion): mass calculated for C 24 H 31 CIN 4 O, 426.22; m / z found, 427.4 [M + Hf.

EXAMPLE 160 4-Chloro-2-. { 3-chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C22H26Cl2N4O, 432.15; m / z found, 433.3 [M + Hf.

EXAMPLE 161 2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-fluoro-4-metif-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H28CIFN4O, 430.19; m / z found, 431.4 [M + Hf.

EXAMPLE 162 2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} 4,6-dimethyl-1H-benzoimidazole MS (electroaspersion): mass calculated for C 24 H 31 CIN 4 O, 426.22; m / z found 427.4 [M + Hf.

EXAMPLE 163 6-Chloro-2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-methyl-1H-benz? Imidazole MS (electroaspersion): mass calculated for C23H28CI2N4O, 446.16; m / z found, 446.4 [M + Hf.

EXAMPLE 164 -Chloro-2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-methyl-1H-benzoimidazole EM (electroaspersion): mass calculated for C23H28CI2N4O, 446.16; m / z found, 446.4 [M + Hf.

EXAMPLE 165 -Fluoro-4-methyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole A. 5-Bromo-2-f4 - (- methyl-piperidin-4-yl) -butoxy-pyridine. To a solution of 4- (1-methyl-piperidin-4-yl) -butan-1-ol (14.9 g, 86.9 mmol, 1.0 equiv.) In DMF (180 mL) at 0 ° C was added sodium hydride ( 60% dispersion in oil 4.86 g, 122 mmol, 1.4 equiv.). The mixture was heated at room temperature for 1 hr, and then cooled again to 0 ° C. A solution of 5-bromo-2-chloro-pyridine (20.6 g, 86.9 mmol, 1.0 equiv.) In DMF (20 mL) was added dropwise. The mixture was stirred at room temperature for 18 hr, then diluted with water (100 ml) and saturated aqueous NaHCO 3 (250 ml). The mixture was extracted with chloroform (3 x 100 ml) and the combined extracts were concentrated. Purification by method 2 gave 8.82 g of 5- bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine as a mixture with several unidentified impurities. EM (electroaspersion): mass calculated for Ci5H23BrN20, 326. 10; m / z found, 327.3 [M + Hf. B. 5-Fluoro-4-methyl-2- (5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy-pyridin-4-yl-1H-benzoimidazole. of LDA (2.0 M in THF, 18.2 ml, 36.4 mmoles, 2.2 equiv.) at -78 ° C in a oven-dried 100 ml round-bottom flask was added dropwise a solution of 5-bromo-2- [ 4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine (5.40 g, 16.6 mmol, 1.0 equiv.) In THF (20 mL) The solution was stirred at -78 ° C for 45 min. then DMF (6.05 ml, 82.8 mmol, 5.0 equiv.) was added dropwise.The solution was quenched with saturated aqueous NaHCO3 (25 ml) and extracted with chloroform (3 x 50 ml) .The combined extracts were washed with brine. The crude residue was diluted with ethanol (5 ml) and treated with sodium bisulfite (2.1 g) The precipitate that formed was collected by vacuum filtration and washed with diethyl ether. chloroform (50 ml) and washed with saturated aqueous NaHCO3 (50 ml) The organic layer was dried (Na2SO), filtered and concentrated to give 5-bromo-2- [4- (1-methyl-piperdin-4-yl) -butoxy] -pyridine-4-carbaldehyde as a mixture with some other unidentified products. A solution of this crude mixture in methanol (15 ml) was treated with concentrated H2SO4 (1 ml) and the resulting solution was stirred for 14 hr. The mixture was diluted with saturated aqueous NaHCO3 (25 ml) and extracted with chloroform (3 x 25 ml). The combined extracts were concentrated to give 5-bromo-4-dimethoxymethyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine. A solution at -78 ° C of the pyridine (2.0 g, 5.0 mmol, 1.0 equiv.) In THF (50 ml) was treated with n-butyllithium (2.5 M in hexanes, 2.2 ml, 5.5 mmol, 1.1 equiv. ). The solution was stirred for 30 minutes, and then methyl iodide (0.312 g, 5.0 mmol, 1.0 equiv.) Was added. After 30 min, the reaction was quenched with saturated aqueous NaHCOs (10 mL) and extracted with chloroform (3 X 25 mL). The combined extracts were dried (Na2SO4), filtered and concentrated to give 4-dimethoxymethyl-5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine as a crude mixture. A solution of 4-dimethoxymethyl-5-methyl-2- [4- (1-methyl-p-peridin-4-yl) -butoxy] -pyridine (0.64 mg) in THF (100 ml) was treated with 1.0 M HCl. (20 ml) and the mixture was stirred for 4 h. The mixture was diluted with saturated aqueous NaHCOß and extracted with chloroform (3 × 100 ml). The combined extracts were dried (Na 2 S 4), filtered and concentrated to give 5-methyI-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine-4-carbaldehyde. A portion of this aldehyde (110 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (60 mg), and Na 2 SO 5 (100 mg) were stirred in DMF (2 ml) at 90 ° C for 36 hr. The reaction mixture was concentrated and purified by reverse phase CLAP to give the title compound. EM (electroaspersion): mass calculated for C24H31FN4O, 410.25; m / z found, 411.5 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 8.17 (s, 1 H), 7.54-7.43 (m, 1 H), 7. 19-7.05 (m, 2H), 4.34 (t, J = 6.4 Hz, 2H), 3.53-3.43 (m, 2H), 3.04-2.89 (m, 2H), 2.84 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H), 2.06-1.95 (m, 2H), 1.85-1.76 (m, 2H), 1.64-1.29 (m, 7H). The following compounds in Examples 166-168 were prepared according to the procedures described for Example 165.

EXAMPLE 166 -Chloro-6-fluoro-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C23H28CIFN4O, 430.19; m / z found, 431.4 [M + Hf.

EXAMPLE 167 -tert-Butyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzo i midazole EM (electroaspersion): mass calculated for C27H38N4O, 434.30; m / z found, 435.5 [M + Hf.

EXAMPLE 168 4,5-Dimethyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C25H34N4O, 406.27; m / z found, 407.5 [M + Hf.

EXAMPLE 169 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} 4,6-dimethyl-1H-benzoimidazole The title compound was prepared as described in Example 165, using hexachloroethane in place of methyl iodide. EM (electroaspersion): mass calculated for C24H31CIN4O, 426. 22; m / z found, 427.4 [M + Hf. The following compounds in Examples 170-172 were prepared according to the procedures described in Example 169.

EXAMPLE 170 -Chloro-2-. { 5-Chloro-2- [4- (1-methyl-p -peridin-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazoi EM (electroaspersion): mass calculated for C22H26Cl2N40, 432. fifteen; m / z found 433.3 [M + Hf.

EXAMPLE 171 -Chloro-2-. { 5-chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -6-fluoro-1 H- benzoimidazole EM (electroaspersion): mass calculated for C22H25CI2FN 0, 450. 14; m / z found 451.3 [M + Hf.

EXAMPLE 172 -tert-Butyl-2-. { 5-Chloro-2- [4- (1-methyl-p-piperidn-4-yl) -butoxy] -pyridin-4-yl} -1H- benzoimidazole EM (electroaspersion): mass calculated for C26H35CIN4O, 454.25; m / z found 455.5 [M + Hf. The following compounds in Examples 173-175 were prepared according to the procedures described for Example 128.

EXAMPLE 173 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-chloro-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H26BrCIN 0, 476.10; m / z found 477.3 [M + Hf.

EXAMPLE 174 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-6-fluoro-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H25BrClFN 0.494.09; m / z found 495.3 [M + Hf.

EXAMPLE 175 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-1H-benzoimidazole EM (electroaspersion): mass calculated for C22H26BrCIN4 ?, 476. 10; m / z found 477.3 [M + Hf.

EXAMPLE 176 . { 2- (5-Fluoro-4-methyl-1 H -benzoimidazol-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -methanol A. 4- [3-4-Bromo-3- [1,3] dioxan-2-yl-phenoxy) -propyl-1-methyl-piperidine. To a solution of 3- (1-methyl-plperidin-4-yl) -propan-1-ol (7.07 g, 45 mmol, 1.0 equiv.) And methanesulfonyl chloride (4.18 mL, 54 mmol, 1.2 equiv.) In dichloromethane (100 ml) at 0 ° C triethylamine (9.41 ml, 68 mmol, 1.5 equiv.) was added. The reaction mixture, which was allowed to warm to room temperature, was stirred for 30 minutes and then emptied into saturated aqueous NaHCO3. The aqueous mixture was extracted with chloroform and then ethyl acetate. The combined extracts were dried (Na2SO), filtered and concentrated. The residue was dissolved in acetonitrile (100 ml) and 4-bromo-3- [1,3] dioxan-2-yl-phenol (11.7 g, 45 mmol, 1.0 equiv.) And cesium carbonate (29.2 mg, 90 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 12 hr, then heated at 50 ° C for 1.0 hr. The mixture was poured into saturated aqueous NaHCO3 and extracted with ethyl acetate (2x) and chloroform. The combined extracts were dried (Na2SO4), filtered and concentrated. Purification by method 2 gave 4.82 g (27%) of the title compound. 1 H NMR (400 MHz, CD 3 OD): 7.43 (d, J = 8.8 Hz, 1 H), 7.19 (d, J = 3.1 Hz, 1 H), 6.83 (dd, J = 8.8.3.1 Hz, 1 H), 5.72 ( s, 1 H), 4.27-4.19 (m, 2H), 4.10-4.00 (m, 2H), 3.97 (t, J = 6.4 Hz, 2H), 2.93-2.85 (m, 2H), 2.28 (s, 3H) ), 2.25-2.11 (m, 1 H), 2.07-1.97 (m, 2H), 1.85-1.72 (m, 4H), 1.52-1.21 (m, 6H). B. 2- (2-f 1, 3) Dioxan-2-yl-4-3- (1-methyl-piperidin-4-yl) -propoxyl-phenyl.) - 5-fluoro-4-methyl-1 H-benzoimidazole To a stirred solution of 4- [3- (4-bromo-3- [1,3] dioxan-2-yl-phenoxy) -propyl] -1-methyl-piperidine (4.82 g, 12.4 mmol. , 1.0 equiv.) In THF (62 ml) at -78 ° C was added 2.5 M n-butyllithium in hexanes (22 ml, 55 mmol, 4.4 equiv.) The resulting orange solution was stirred for 30 minutes, then DMF (9.6 ml, 124 mmol, 10.0 equiv.) was added.The solution was warmed to room temperature and stirred for 1.0 hr, then cooled again to -78 ° C and saturated aqueous NaHCO3 was added. at room temperature, it was poured into water, and extracted with ethyl acetate.The combined extracts were dried (Na2SO4), filtered and concentrated.The crude residue was partially purified by method 2. 2- [1, 3 ] resulting dioxan-2-yl-4- [3- (1-methy1-piperidin-4-yl) -propoxy] -benzaldehyde (491 mg, 1.41 mmol, 1.0 equiv.) was stirred with 4-f! Uoro-3-methyl-benzene-1,2-diamine (198 mg, 1.41 mmol, 1.0 equiv.) And Na 2 S 2? S (350 mg, 1.84 mmol, 1.3 equiv.) In DMF (7.0 ml) a 90 ° C for 2 hr. The mixture was loaded onto silica gel and purified by method 2 to give 509 mg (77%) of the title compound. EM (electroaspersion): mass calculated for C27H34FN303,467.26; m / z found, 468.4 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.62 (d, J = 8.5 Hz, 1 H), 7.44-7.37 (m, 1 H), 7.35 (d, J = 2.7 Hz, 1 H), 7.09-6.99 (m , 2H), 5.97 (s, 1 H), 4.19-4.13 (m, 2H), 4.09 (t, J = 6.4 Hz, 2H), 3.95-3.86 (m, 2H), 2.95-2.87 (m, 2H) , 2.53 (s, 3H), 2.30 (s, 3H), 2.22-1.99 (m, 3H), 1.93-1.76 (m, 4H), 1.51-1.22 (m, 6H). O 2- (5-Fluoro-4-metii-1 H-benzoimidazol-2-yl) -5- [3-1 -methyl-p-per'd¡n-4-yl) -propoxy-1-phenyl) -methanol . 2-. { 2- [1, 3] Dioxan-2-yl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} 5-fluoro-4-methyl-1H-benzoimidazole (401 mg) and p-toluenesulfonic acid (1.0 g) were stirred in an acetone solution (10 ml) and water (1.0 ml) at reflux for 16 hr. The solution was poured into saturated aqueous NaHC03 and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated. A portion of the crude residue (43.3 mg) was dissolved in ethanol (2.0 ml) and sodium borohydride (300 mg) was added. The mixture was stirred for 1.0 hr and then emptied into saturated aqueous NaHCO3. The aqueous mixture was extracted with ethyl acetate and the combined extracts were dried (Na S04), filtered and concentrated. The residue was purified by method 2 to give 6.0 mg of the title compound. MS (electroaspersion): mass calculated for C24H30FN3O2, 411.23; m / z found, 412.4 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 7.82 (d, J = 8.6 Hz, 1 H), 7.43-7.33 (m, 1 H), 7.14-7.10 (m, 1 H), 7.06-6.97 (m, 2H). , 4.72 (s, 2H), 4.09 (t, J = 6.3 Hz, 2H), 2.94-2.86 (m, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.11-1.99 (m, 2H) ), 1.91-1.74 (m, 4H), 1.52-1.42 (m, 2H), 1.41-1.21 (m, 4H).

EXAMPLE 177 . { 4- (4,6-Dimethyl-1 H-benzoimidazol-2-yl) -6- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-3-yl} -methanol 5-Bromo-4-dimethoxymethyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine (0.5 g, 1.25 mmol, 1.0 equiv.) was dissolved in THF (6 ml) and cooled to -78 ° C. A 2.5 M solution of n-butyl lithium in hexanes (0.6 ml, 1.5 mmol, 1.2 equiv.) Was added dropwise. The solution was stirred for 45 minutes, and then DMF (0.55 ml, 1.25 mmol, 1.0 equiv.) Was added. After 1 hr, sodium borohydride (38 mg, 1.36 mmol, 1.1 equiv.) Was added. The mixture was allowed to warm to -40 ° C for 30 minutes, then quenched with saturated aqueous NaHCO3 (10 mL). The mixture was extracted with chloroform (3 X 30 ml), and the combined extracts were dried (Na2SO4), filtered and concentrated to give. { 4-dimethoxymethyl-6- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-3-yl} -methanol as a raw mixture. This matter! Crude (88 mg) was dissolved in THF (3 ml) and 1.0 M HCl (3 ml) was added in portions over 3 hr at 60 ° C. The mixture cooled, saturated aqueous NaHCO3 was added, and the mixture was extracted with chloroform (3 X 30 ml). The combined extracts were dried (Na2SO4), filtered and concentrated. A portion of the resulting crude 5-hydroxymethyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridine-4-carbaldehyde (33 mg), 3,5-dimethyl-benzene-1, 2 Diamine (22 mg), and Na2S205 (36 mg) were stirred in DMF (2 ml) at 90 ° C for 36 hr. The reaction mixture was purified by method 2 to give 5.3 mg of the title compound. EM (electroaspersion): mass calculated for C25H34N4O2, 422.27; m / z found, 423.5 [M + Hf. 1 H NMR (400 MHz, CD 3 OD): 8.21 (s, 1 H), 7.30 (s, 1 H), 7.23 (br s, 1 H), 6.95 (br s, 1 H), 4.68 (s, 2 H), 4.34 (t , J = 6.4 Hz, 2H), 2.95-2.82 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.11-1.98 (m, 2H), 1.86- 1.68 (m, 4H), 1.57-1.44 (m, 2H), 1.39-1.15 (m, 5H).

BIOLOGICAL EXAMPLES Binding test on recombinant human histamine H4 receptor SK-N-MC cells or COS7 cells were transiently transfected with pH4R and grown in 150 cm2 tissue culture layers. The cells were washed with saline, scraped with a cell scraper and collected by centrifugation (1000 rpm, 5 min). The cell membranes were prepared by homogenizing the cell pellet in 20 mM Tris-HCl with a polytron tissue homogenizer for 10 seconds at high speed. The homogenate was centrifuged at 1000 rpm for 5 minutes at 4 ° C. The supernatant was then collected and centrifuged at 20,000 x g for 25 minutes at 4 ° C. The final pellet was resuspended in 50 mM Tris-HCl. The cell membranes were incubated with 3H-histamine (5-70 nM) in the presence or absence of excess histamine (10,000 nM). Incubation occurred at room temperature for 45 minutes. Membranes were harvested by rapid filtration on filters Whatman GF / C and washed 4 times with 50 mM ice-cold Tris HCl. The filters were then dried, mixed with scintillant and counted for radioactivity. SK-N-MC or COS7 cells expressing human histamine H4 receptor were used to measure the binding affinity of other compounds and their ability to displace 3H-ligand binding by incubating the above-described reaction in the presence of various concentrations of inhibitor. or compound that has to be tested. For competition binding studies using 3H-histamine, K1 values were calculated based on an experimentally determined KD value of 5 nM and a ligand concentration of 5 nM, in accordance with Y.-C. Cheng and W.

H. Prusoff (Biochem Pharmacol, 1973, 22 (23): 3099-3108): K, = (Cl50) / (1 + Union test results PICTURE Ahem. ? Ahem? K | Ahem. Ki Ahem K, (nM) (nM) (nM) (nM) 1 46 45 110 89 120 134 117 2 9 46 113 90 73 135 47 3 21 47 129 91 633 136 1 4 26 48 154 92 113 137 3 43 49 173 93 7 138 46 6 61 50 187 94 13 139 69 7 66 51 278 95 4 140 144 8 138 52 641 96 1 141 60 9 250 53 872 97 25 142 73 89 54 30 98 28 143 6 11 59 55 203 99 38 144 8 12 224 56 324 100 41 145 3 13 257 57 17 101 55 146 5 14 497 58 101 102 321 147 8 22 59 86 103 41 148 17 16 16 60 39 104 266 149 4 17 136 61 49 105 85 150 19 18 64 62 51 106 12 151 21 19 18 63 57 107 26 152 117 65 64 121 108 31 153 179 21 84 65 157 109 6 154 111 22 1 66 32 110 6 155 13 23 103 67 1 111 21 156 20 24 109 68 5 112 6 157 28 119 69 6 113 4 158 21 26 142 70 20 114 11 159 19 27 74 71 26 115 4 160 53 28 9 72 5 116 12 161 20 29 326 73 69 117 5 162 15 22 74 22 118 4 163 12 31 9 75 28 119 51 164 7 32 93 76 121 120 94 165 3 33 81 77 4 121 60 166 6 34 112 78 21 122 71 167 4 28 79 14 123 67 168 6 36 35 80 128 124 86 169 1 37 36 81 150 125 77 170 5 38 65 82 23 126 427 171 12 39 66 83 161 127 773 172 1 40 74 84 267 128 3 173 21 41 78 85 39 129 5 174 31 42 79 86 103 130 5 175 6 43 82 87 61 131 3 176 4 44 87 88 52 132 5 177 4 133 12 Mast cell chemotaxis test The accumulation of mast cells in the mucosal epithelium is a well-known feature of allergic rhinitis and asthma. In addition, it is known that numbers of mast cells increase in a number of inflammatory conditions. Some of this is due to chemotaxis of mast cells to sites of inflammation. Chemotaxis for specific agents can be simulated in vitro. Wells Transweils (Costar, Cambridge, MA) with a pore size of 8 μm are coated with 100 μl of 100 ng / ml human firbonectin (Sigma) for 2 hours at room temperature. After the removal of fibronectin, 600 μl of RPMI with 5% BSA, in the presence of 10 μM histamine, is added in the lower chamber. To test the various histamine receptor (HR) antagonists, 10 μM and / or 1 μM solutions of the test compounds are added to the upper and lower chambers. The mast cells (2x105 / well) are added to the upper chamber. The plates are incubated for 3 hours at 37 ° C. The Transweils wells are removed and the cells in the lower chamber are counted for sixty seconds using a flow cytometer. The HR inhibition data are therefore obtained.

H4 cell expression type distribution RNA was prepared from the different cells using an RNeasy kit (Qiagen, Valencia, CA) in accordance with the manufacturer's instructions. Total RNA was extracted from purified human cells using RNeasy equipment (Qiagen, Valencia, CA) and reverse transcribed to cDNA using the RT reaction kit (Invitrogen) in accordance with the manufacturer's instructions. H receptor RNA was detected by RT-PCR using specific primers of human H receptor 5'-ATGCCAGATACTAATAGCACA and 5'-CAGTCGGTCAGTATCTTCT. The band Amplified PCR for H receptor is 1170 bp.

Results The results of RT-PCR indicate that the H4 receptor is expressed in mast cells, dendritic cells, basophils and eosinophils. These positive results are consistent with published literature (eg, Oda et al., Nguyen et al., And Morse et al., In the background section). The accumulation of barleys and eosinophils in affected tissues is one of the main characteristics of allergic rhinitis and asthma. Since H receptor expression is found in these cell types, H4 receptor signaling is likely to mediate the infiltration of mast and eosinophil cells in response to histamine. The following table reports the cell-type distribution of H4 expression by RT-PCR.

Species Type of cell H Human Eosinophils + Immature dendritic cells + Mature dendritic cells + Mast cells + Basophils + CD14 monocytes "CD4 + T cells + CD8 + T cells Neutrophil B cells Mouse / (rat) Eosinophils + Peritoneal mast cells (rat) + Mast cells derived from bone marrow + immature dendritic cells + mature dendritic cells + macrophages derived from bone marrow peritoneal macrophages CD4 + T cells + CD8 + T cells B cells Inhibition of eosinophilic shape change by histamine H4 receptor antagonists The accumulation of eosinophils at sites of allergic reaction is a well-known feature of allergic rhinitis and asthma. This example demonstrates that histamine H4 receptor antagonists can block the shape-shifting response in human eosinophils in response to histamine. The change of form is a cellular characteristic that precedes the chemotaxis of eosinophils.

Methods Human granulocytes were isolated from human blood by a Ficoll gradient. Red blood cells were used with 5-1 OX Qiagen lysis pH regulator at room temperature for 5-7 minutes. The granulocytes were harvested and washed once with pH-regulator FACS. The cells were resuspended at a density of 2 x 106 cells / ml in a reaction pH regulator. To test the inhibition by specific histamine receptor antagonists, 90 μl of the cell suspension (~ 2 x 10 5 cells) was incubated with 10 μM of one of the various test compound solutions. After 30 minutes, 11 μl of one of the various concentrations of histamine were added. Ten minutes later the cells were transferred to ice and fixed with 250 μl of ice-cold fixative pH buffer (2% formaldehyde) for 1 minute. The shape change was quantified using a forward scattering test by fixed autofluorescence (GAFS) (S.A. Bryan et al., Am. J. Respir. Crit. Care Med. 2002, 165 (12): 1602-1609).

Results - histamine mediates eosinophil shape change through H4 receptor The change in eosinophil shape is due to cytoskeletal changes that precede chemotaxis and therefore is a measure of chemotaxis. The data in the following table show that histamine induces a dose-dependent change in eosinophils. Histamine receptor (HR) antagonists were used to determine which histamine receptor is responsible for the change in shape. Specific antagonists for the histamine receptor Hi (diphenhydramine) or the H2 receptor (ranatidine) do not alter the change of histamine-induced form. However, a double H3 / H4 antagonist (thioperamide) and a specific histamine H4 receptor antagonist ((5-chloro-1H-indol-2-yl) - (4-methyl-piperazin-1-yl) -methanone , K, = 5 nM) inhibited the eosinophil shape change induced by histamine with an IC 50 of 1.5 and 0.27 μM, respectively.

Inhibition of eosinophil chemotaxis by histamine H receptor antagonists The accumulation of eosinophils at allergic reaction sites is a well-known feature of allergic rhinitis and asthma. Eosinophils are purified from human blood with standard methods. Chemotaxis tests are carried out using Transweils wells (Costar, Cambridge, MA) with a pore size of 5 μm coated with 100 μl of 100 ng / ml human fibronectin (Sigma) for 2 hours at room temperature. After the removal of fibronectin, 600 μl of RPMI with 5% BSA in the presence of histamine (varying from 1.25-20; μM) is added to the lower chamber. To test the various histamine receptor antagonists, 10 μM of the test compounds can be added to the upper and lower chambers. Eosinophils will be added to the upper chamber while histamine or chemotactic factors will be placed in the lower chamber. The plates are incubated for 3 hours at 37 ° C. The transweil wells are removed and the number of cells in the lower chamber can be counted for 60 seconds using a flow cytometer, or can be quantified using Giemsa stain.

Inhibition of Zymosan Induced Peritonitis in Mice by Histamine H4 Receptor Antagonists It has been shown that histamine H4 receptor antagonists can block peritonitis induced by zymosan, which is the insoluble polysaccharide component on the cell wall of Saccharomyces cerevisiae. This is commonly used to induce peritonitis in mice and appears to act in a mast cell-dependent manner. The compounds of the present invention can be tested in said model to demonstrate their use as anti-inflammatory agents. At time 0, mice, compound or PBS, are given either s.c. or p.o. Fifteen minutes later, each mouse receives 1 mg of zymosan A (Sigma) i.p. The mice are sacrificed 4 hours later, and the peritoneal cavities are washed with 3 ml of PBS containing 3 mM EDTA. The number of migrated leukocytes is determined by taking an aliquot (100 μl) of the washing fluid and diluting 1: 10 in Turk's solution (0.01% crystal violet in 3% acetic acid). The samples are then subjected to swirling action, and 10 μl of the stained cell solution is placed in a Neubauer hemocytometer. Differential cell counts are made using an optical microscope (Olympus B061). In view of their chromatic characteristics and their appearance of nucleus and cytoplasm, polymorphonuclear leukocytes (PMN;> 95% neutrophils) can be easily identified. Treatment with zymosan increases the number of neutrophils that is representative of an inflammatory response. Treatment with H 4 receptor antagonists blocks this increase.

Inhibition of mast cell auimiotaxis by an H4 receptor antagonist in an animal model of asthma and allergic rhinitis An animal model is used to test the observation that mast cells accumulate in response to allergic inflammation and that this can be blocked by antagonists. of H receptor. The compounds of the present invention can be tested in this model to demonstrate their use as a treatment for allergic rhinitis or asthma. Mice are sensitized by intraperitoneal injection of ovalbumin / alum (10 μg in 0.2 ml AI (OH) 3, 2%) on day 0 and day 14. On day 21 to day 23 the mice are challenged by PBS or ovalbumin, and sacrificed 24 hours after the last challenge on day 24. A section of the trachea is removed and fixed in formalin. Longitudinal sections of tracheas embedded in paraffin are performed followed by staining of mast cells with toluidine blue. Altematively, the tracheas are frozen in OCT for sectioning under freezing, and the mast cells are identified by staining with IgE. The mast cells are quantified as submucosa or subepithelium depending on their location within each section of the trachea. Exposure to allergen can increase the number of subepithelial mast cells and this effect is blocked by H receptor antagonists. The features and advantages of the invention are apparent to one skilled in the art. Based on this description, including the brief description, detailed description, background, examples and claims, one skilled in the art will be able to make modifications and adaptations to various conditions and uses. Publications described herein are incorporated by reference in their entirety. These other embodiments are also within the scope of the invention.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula (I) or (II): wherein W is N or CR7; X is N or CH; And it is O, NR12, or CR12R13; Z is N or CR14; n 0, 1, or 2; each of R 1"4 is, independently of other assignments of substituents, H, C 1-4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, C 4 alkoxy, alkylamino C1-4, C? -4 alkylthio, C 1-4 alkylsulfonyl, C 3-6 cycloalkyl, -OCH 2 Ph, cyano, -CF 3, F, Cl, Br, I, nitro, -OCF 3, -SCF 3, -ORG , -SR °, -S (0) Rc, -S02Rc, -C (0) R °, phenyl, benzyl, phenethyl, -C (0) NRaRb, -C (0) ORc, -NRaRb, -CH2NRaRb or - CH2ORc, wherein each of Ra, Rb and Rc is, independently of other alloy assignments, selected from H, C1-4 alkyl, C3.6 cycloalkyl, phenyl, (C3-6 cycloalkyl) C alkyl? -2-, benzyl and phenethyl, or Ra and Rb taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring HetCyd, wherein said ring HetCyd has 0 or 1 additional heteroatoms selected from O, S, > NH " C-C6 alkyl, and wherein any phenyl, phenethyl, benzyl, alkyl or cycloalkyl portion in any One of said R1"4, Ra, Rb, Rc, and the ring HetCyd is optionally, and independently of other assignments of substituents, substituted with 1, 2 or 3 substituents selected from C? -3 alkyl, halogen, hydroxy, amino , and C? -3 alkoxy; each of R5"7 is, independently of other assignments of substituents, H, C1-6 alkyl, F, Cl, Br, I, CF3, -OCF3, -ORc, -SRC, -S (0) Rc, - S02Rc, C1-4 alkoxy, cyano, nitro, -C (0) NRaRb, -C (0) phenyl, -C (0) -alkyl of C? -6, -S (O) alkyl of C1.4, or -S02alkyl of C? _4; o, R5 and R6 for a compound of the formula (I) taken together with the carbon atoms to which they are attached form a cyclic structure Cyc1 selected from aryl, heteroaryl, 5- or 6-membered carbocycle , and 5 or 6 membered heterocycle with 1 or 2 heteroatoms, wherein said Cyc1 cyclic structure is, independently of other alloy assignments, substituted with 0, 1, or 2 substituents selected from C1.3 alkyl, halogen, hydroxy, amino, and C?-3 alkoxy, or, R 7 and R 6 for a compound of the formula (11) taken together with the carbon atoms to which they are attached form a cyclic structure Cyc 2 selected from aryl, heteroaryl, carbocycle or 6 members and het 5- or 6-membered heterocycle with 1 or 2 heteroatoms, wherein said cyclic structure Cyc2 is, independently of other substituent assignments, substituted with 0, 1, or 2 substituents selected from C1.3 alkyl, halogen, hydroxy, amino, and C1.3 alkoxy; R8 is H, C? -6 alkyl, C? - alkoxy, or OH; each of R9 and R10 is, independently of other assignments of substituents, H or C? _? alkyl, or R9 and R0 taken together form a cyclic structure of 5-6 Cyc3 members, wherein said Cyc3 cyclic structure is a 5- or 6-membered carbocycle or a 5- or 6-membered heterocycle with 1 or 2 heteroatoms, and wherein said Cyc3 cyclic structure is, independently of other alloy assignments, substituted with 0, 1 or 2 substituents selected from C1-6alkyl 3, halogen, hydroxy, amino, and C1-3 alkoxy; R11 is H or C1-4 alkyl; each of R12 and R13 is, independently of other assignments of substituents, H or C1- alkyl; or, when Y is CR12R13, R 2 and R 13 taken together with the carbon member to which they are attached form an optionally substituted cyclic structure Cyc 4, wherein said cyclic structure Cyc 4 is a 3- to 6-membered carbocycle or a 3-membered heterocycle 6 members with 0 or 1 additional heteroatoms, or CR12R13 is C = 0; R14 is H, C? -4 alkyl, OH, or C? -4 alkoxy; an enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt, amide or ester thereof; provided that: when Y is O or NR12, then Z is CR14 and R8 is not OH or C? - alkoxy; when Z is N, Y is CR12R13; and neither of R1 nor R4 is C (0) NH2.
2. The compound according to claim 1, further characterized in that W is N or CR7.
3. The compound according to claim 1, further characterized in that X is N or CH.
4. The compound according to claim 1, further characterized in that Y is CR12R13.
5. The compound according to claim 1, further characterized in that Y is CH2.
6. The compound according to claim 1, further characterized in that Z is N or CH.
7. The compound according to claim 1, further characterized in that n = 1 or 2.
8. The compound according to claim 1, further characterized in that n = 1.
9. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, F, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido and CH2OMe.
10. The compound according to claim 1, further characterized in that R1 is H, methyl, F or Cl.
11. The compound according to claim 1, further characterized in that R2 is selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, CF 3, OCF 3, F, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido and benzoyl.
12. The compound according to claim 1, further characterized in that R 2 is H, F, Cl, methyl, CF 3, OCF 3, or t-butyl.
13. The compound according to claim 1, further characterized in that R3 is selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, CF3, OCF3, F, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido and benzoyl.
14. The compound according to claim 1, further characterized in that R3 is H, F, Cl, methyl, CF3, OCF3, or t-butyl.
15. The compound according to claim 1, further characterized in that R4 is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, R, Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido and CH2OMe.
16. The compound according to claim 1, further characterized in that R4 is H, methyl, F or Cl.
17. The compound according to claim 1, further characterized in that one or more of R1"4 are not H 18. The compound according to claim 1, further characterized in that R5 is H, F, Cl, methyl or ethyl 19. The compound according to claim 1, further characterized in that R5 is F, Cl, methyl , hydroxymethyl, hydroxyethyl, pyrrolidinylmethyl or diethylaminomethyl 20. The compound according to claim 1, further characterized in that R is H, F, Cl or methyl. 21. - The compound according to claim 1, further characterized in that R7 is H, F, Cl or methyl. 22. The compound according to claim 1, further characterized in that R5 is Cl, methyl or hydroxymethyl. 23. The compound according to claim 1, further characterized in that R8 is H, methyl or OH. 24. The compound according to claim 1, further characterized in that R8 is H. The compound according to claim 1, further characterized in that R9 and R10 are, independently, selected from the group consisting of a) H , b) methyl, ethyl, propyl, isopropyl and c) trifiuoromethyl. 26. The compound according to claim 1, further characterized in that each of R9 and R10 is, independently, H or methyl. 27. The compound according to claim 1, further characterized in that R11 is H, methyl or ethyl. 28. The compound according to claim 1, further characterized in that R11 is mephyl. 29.- A compound selected from: 2-. { 2-Chloro-4- [3- (4-metii-piperazin-1-yl) -propoxy] -phenyl} -4,5-dimethyl-1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-l) -propoxy] -phenyl} -5-trifluoromethoxy-1 H-benzoimidazole; 5-fer-Butyl-2-. { 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxl] -phenyl} -1 H-benzoimidazole; 5-tert-Butyl-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 4,5-Dimethyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-fer-Butyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 5-fer-ButiI-2-. { 3- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole; (1 - { 3- [4- (5-tert-Butyl-1 H-benzoimidazol-2-yl) -2-chloro-phenoxy] -propyl] -pyrrolidin-3- il) -dimethylamine; 5-Chloro-2-. { 3-chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -6-methyl-1 H-benzoimidazole; 2-. { 3-Fluoro-4- [3- (4-methyl-p-piperazin-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 5-Met.l-2-. { 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -naphthalene-1-yl} -1 H-benzoimidazole; 4- [3- (5-Fer-Butyl-1H-benzoimidazol-2-yl) -phenoxy] -1- (4-methyl-p-piperazin-1-yl) -butan-1-one; 5-Chloro-2- [3-chloro-4- (3-piperazin-1-yl-propoxy) -phenyl] -6-fluoro-1 H-benzoimidazole; 5-fer-Butl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole; 2-. { 2-Chloro-4- [3- (1-methyl-p-peridin-4-yl) -propoxy] -phenyl} -4,6-dimethyl-1 H-benzoimidazole; 2-. { 2-Chloro-4- [2-methyl-3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -17 4-methyl-1 H-benzoimidazole; 5-Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6-methyl-1 H-benzoimidazole; 6-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1 -ii) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 5-tert-Butyl-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4,6-dimethyl-1 H-benzoimidazole; 5-Chloro-6-metii-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-6-fluoro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methyl-1 H-benzoimidazole; 5,6-Difluoro-2-. { 3-fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -fenii} -1 H-benzoimidazole; . 2-. { 3-Fluoro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl) - [1,4] diazepan-1-yl) -propoxy] -pheni)} -4,5-dimethyl-1 H-benzoimidazole; 5,6-Dimethyl-2-. { 3- [4- (4-methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-metii-piperazin-1-yl) -propoxl] -phenyl} -4,6-dimethyl-1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 5-tert-Butyl-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; -. { 3-Methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1H-benzoimidazole; 5-Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6-fluoro-1 H-benzoimidazole; 5,6-Dichloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzoimidazole; 5-Chloro-2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -6-fluoro-1 H-benzoimidazole; 5-Chloro-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methyl-1 H-benzoimidazole; 5,6-Dichloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-6-methyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1 -ii) -propoxy] -phenyl} -5-methyl-1 H-benzoimidazole; 5-Chloro-2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1H-benzoimidazole; 5-Chloro-6-fluoro-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Methyl-2-. { 3-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 3-Met l-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; -. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-6-fluoro-2-. { 3-methoxy-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 3-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-methoxy-1 H-benzoimidazole; 5-tert-Butyl-2-. { 3,5-dibromo-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -pheni} -1 H-benzoimidazole; 2-. { 2-Methoxy-4- [3- (4-methyl-piperazin-1-ii) -propoxy] -phenyl} -5-trifluoromethyl-1H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-trifluoromethyl-1 H-benzoimidazole; 2-. { 3- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; (2- {3- [4- (4-Methyl-piperazin-1-yl) -butoxy] -phenyl} -1 H -benzoimidazol-5-yl) -phenyl-methanone; 6-Chloro-2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 5-tert-Butyl-2-. { 3-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4,5-dimethyl-1 H-benzoimidazole; 5-Chloro-6-methyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-2-. { 4- [3- (1-methyl-piperidin-4-ii) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-6-fluoro-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-tert-Butyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzolmidazole; 5-Methyl-2-. { 4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2-. { 4- [3- (1-Methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 6-Chloro-2-. { 2-fluoro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 5-Fluoro-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 4-Chloro-2-. { 2-methyl-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 6-Chloro-4-methyl-2-. { 2-methyl-4- [3- (1-methyl-p-perdid-4-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-2-. { 2-Chloro-4- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -6-fluoro-1H-benzoimidazoI; 2-. { 2-CIORO-4- [3- (1-methyl-piper-dine-4-yl) -propoxy] -phen} -3H-naphtho [1,2-d] imidazole; 4,6-DimetiI-2-. { 2-methyl-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -pheni !} -1H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl-p-piperazin-1-yl) -propoxy-Henyl} -4-methyl-1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5-fluoro-4-methyl-1 H-benzoimidazole; 2-. { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -3H-naphtho [1,2-d] imidazole; 6- { 2-Chloro-4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -5H- [1, 3] dioxolo [4 ', 5': 4,5] benzo [1,2-d] imidazole; 6-Chloro-2-. { 2-Chloro-4- [3- (4-methyl- [1,4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; 2-. { 3-Chloro-4- [3- (4-methyl-1, 4] diazepan-1-yl) -propoxy] -phenyl} -4-methyl-1 H-benzoimidazole; , 6-Dimethyl-2-. { 3- [4- (4-methiI- [1,4] diazepan-1-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 5-Chloro-2-. { 4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -1H-benzolmidazole; 2-. { 4- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 2- (6-Chloro-4-methyl-1 H -benzoimidazol-2-yl) -5- [3- (1-methyl-p-peridin-4-yl) -propoxy] -benzyl} dimethyl amine; . { 2- (5-Fluoro-4-methyl-1H-benzoimidazol-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -benzyl} dimethyl amine; 4-. { 3- [4- (6-Chloro-4-methyl-1 H -benzoimidazol-2-yl) -3-methyl-phenoxy] -propyl} - [1, 4] diazepan-5-one; 4-. { 3- [4- (5-tert-Butyl-1H-benzoimidazol-2-yl) -3-methy1-phenoxy] -propyl} -1-methyl- [1,4] diazepan-5-one; 5-tert-Butyl-2-. { 2-metll-4- [3- (2-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 5-tert-Butyl-2-. { 2-methyl-4- [3- (2-methyl-piperazin-1-yl) -propoxy] -phenyl} -1 H-benzoimidazole; 6-Chloro-4-methyl-2- [2-methyl-4- (3-piperidin-4-yl-propoxy) -phenyl] -1 H -benzoimidazole; 5-Fluoro-4-methyl-2- [2-methyl-4- (3-plperidin-4-yl-propoxy) -phenyl] -1 H -benzoimidazole; 6-Chloro-2-. { 4- [3- (1-ethyl-piperidin-4-yl) -propoxy] -2-methyl-phenyl} -4-methyl-1 H-benzoimidazole; (2- [3-Chloro-4- (4-methyl-1 H-benzoimidazol-2-yl) -phenoxy] -ethyl} -methyl- (1-methyl-piperidn-4-yl) ) -amine: 6-Chloro-4-methyl-2- { 2-methyl-4- [2- (1-methyl-piperidin-4-yloxy) -ethoxy] -phenyl} -1-H-benzoimidazole; 6-Chloro-4-methyl-2- { 2-methyl-4- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] - phenyl.} -1 H-benzoimidazole; 5-Fluoro-4-methyl-2. {2-methyl-4- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4 -yl) -propoxy] -phenyl.} -1 H-benzoimidazole; 6-Fluoro-7-methyl-2- { 3- [4- (1-methylpperiod-4- il) -butoxy] -phenyl.} -1 H-benzoimidazole; 7-Met l-2. {3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl}. -1 H-benzoimidazole; 6,7-Dimethyl-2-. {3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl] -1 H-benzoimidazole; 5-Chloro-7-methyl-2- {3- [4- (1-methyl-p -peridin-4-yl) -butoxy] -phenyl} -1-H-benzoimidazole; 5,7- Dimethyl -2- {2-methyl-3- [4- (1-methyl-piperidin-4-ii) -butoxy] -phenyl}. -1 H-benzoimidazole; 5-Chloro-7-methyl- 2- {2-mephyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1H-benz Oimidazole: 6-Fluoro-7-methyl-2-. { 2-methyl-3- [4- (1-methyl-piperidin-4-yl) -butoxy] -phenyl} -1 H-benzoimidazole; 6-Fluoro-7-methyl-2-. { 3- [3- (1-methyl-piperidin-4-yloxy) -propoxy] -phenyl} -1 H-benzoimidazole; Y . { 2- (5-Fluoro-4-methyl-1 H-benzoimidazol-2-yl) -5- [3- (1-methyl-piperidin-4-yl) -propoxy] -phenyl} -methanol. 30. A compound selected from: 6-Chloro-4-methyl-2-. { 6- [3- (4-methyl-piperazin- -l) -propoxy) -pyridin-3-yl} -1 H-benzoimidazole; 4-Methyl-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 5-Fluoro-4-metiI-2-. { 6- [3- (4-methyl-piperazin-1-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 4-Methyl-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 4,5-Dimethyl-2-. { 6- [3- (1-methii-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimldazole; 4-Chloro-2-. { 6- [3- (1-methyl-piperidin-4-yl) -propoxy] pyridin-3-yl} -1 H-benzoimidazole; 6-Chloro-4-mephile-2-. { 4-methyl-6- [3- (1-methyl-p-peridin-4-yl) -propoxy] -pyridin-3-yl} -1H-benzoimidazole; 4-Methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 5-Fluoro-4-methyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyrin-3-yl} -1 H-benzoimidazole; 4,5-Dimethyl-2-. { 4-methyl-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 4,6-Dimethyl-2-. { 4-methyl-6- [3- (1-methy1-piperidin-4-yl) -propoxy] -pyridin-3-yl} -1H-benzoimidazoI; 4-Chloro-2-. { 4-methyl-6- [3- (1-methyl-p -peridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 2-. { 4-Chloro-6- [3- (1-methyl-p -peridin-4-yl) -propoxy] -pyridin-3-yl} -5-fluoro-4-methyl-1H-benzoimidazole; 2-. { 4-Chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1 H-benzoimidazole; 6-Chloro-2-. { 4-chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1 H-benzoimidazole; 2-. { 4-Chloro-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} 4,6-dimethyl-1 H-benzoimidazole; 2-. { 4-Methoxy-6- [3- (1-methyl-p-peridin-4-y!) -propoxy] -pyridin-3-yl} -4-methyl-1 H-benzoimidazole; 5- Fluoro-2-. { 4-methoxy-6- [3- (1-methyl-piperidin-4-yl) -propoxy] -pyridin-3-yl} -4-methyl-1H-benzoimidazole; 5-Fluoro-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 4-Methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 6-Chloro-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1H-benzoimidazole; 4,5-Dimethyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 4,6-Dimethyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1H-benzoimidazole; 5-Chloro-4-methyl-2-. { 6- [3- (1-methyl-1, 2,3,6-tetrahydro-pyridin-4-yl) -propoxy] -pyridin-3-yl} -1 H-benzoimidazole; 5-Fluoro-4-methyl-2-. { 6- [3- (1-methyl-piperid-4-yl) -propoxy] -4-pyrrolidin-1-methyl-pyridyl-3-yl} -1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4-methyl-1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methy1-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-fluoro-4-methyl-1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-p-peridin-4-ii) -butoxy] -pyridin-4-yl} -6-chloro-4-methyl-1H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methy1-piperidn-4-yl) -butoxy] -pyridin-4-yl} -4,6-dimethyl-1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-Cioro-4-methyl-1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-piperidn-4-yl) -butoxy] -pyridin-4-yl} -5-tert-butyl-1 H-benzoimidazole; 5-tert-Butyl-2-. { 2- [4- (1-methyl-p-pperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-fluoro-4-methyl-1 H-benzoimidazole; 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1 H-benzoimidazole; 4,6-Dimethyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 4-Methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 4,5-D-methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 5-Fluoro-4-methyl-2-. { 2- [4- (4-Methyl-piperazin-1-yl) -butoxy] -p-r-din-4-yl} -1 H-benzoimidazole; 6-Chloro-4-methyl-2-. { 2- [4- (4-methyl-piperazin-1-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 5-Fluoro-4-methyl-2-. { 2- [4- (4-methii- [1,4] diazepan-1-yl) -butoxy] -pyridin-4-ii} -1 H-benzoimidazole; 4,5-Dimethyl-2-. { 2- [4- (4-methyl- [1,4] diazepan-1-yl) -butoxy] -pyridin-4-yl} -1 H- benzoimidazole; 4,6-Dimethyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 4-Mefil-2-. { 2- [4- (1-Met.l.-p.peridin-4-yl) -butoxy] -pyridin-4-yl} -1H-benzoimidazole; 5-Fluoro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 4-Chloro-2-. { 2- [4- (1-methy1-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 4,5-Dimethyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 6-Chloro-4-metii-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 5-Chloro-4-methyl-2-. { 2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; -ter-Butyl-2- [2- (4-pperiodin-4-yl-butoxy) -pyridin-4-yl] -1 H -benzoimidazole; 4,6-Dimethyl-2- [2- (4-piperidin-4-yl-butoxy) -pyridin-4-yl] -1 H -benzoimidazole; 2-. { 2- [4- (1-Ethyl-p -peridin-4-yl) -butoxy] -pyridin-4-yl} -4,5-dimethyl-1 H-benzoimidazole; 4,6-Dimethyl-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 4-Methyl-2-. { 3-methyl-2- [4- (1-methyl-plperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 6-Chloro-4-methyl-2-. { 3-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 2-. { 3-Chloro-2- [4- (1-methyl-piperidin-4-yl-butoxy] -pyridin-4-yl.} -4-methyl-1 H-benzoimidazole; 2- {3 -Cloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} -4,5-dimethyl-1H-benzoimidazole; 4-Chloro-2- {3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl}. -1H-benzoimidazole; 2-3-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} - 5-fluoro-4-methyl-1 H-benzoimidazole; 2-. {3-Chloro-2- [4 - (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} -4,6-dimethyl-1H-benzoimidazole; 6-Chloro-2-. {3-chloro-2 - [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} -4-methyl-1 H-benzoimidazole; 5-Chloro-2-. {3-chloro -2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl.} -4-methyl-1H-benzoimidazoI; 5-Fluoro-4-methyl-2- {.5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butox -pyridin-4-yl}. -1H-benzoimidazole; 5-Chloro-6-fluoro-2-. {5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1-H-benzoimidazole; 5-tert-Butyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4 -ii.}. -1H-benzoimidazole; 4,5-Dimethyl-2-. { 5-methyl-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -4,6-dimethyl-1 H-benzoimidazole; 5-Chloro-2-. { 5-chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -1 H-benzoimidazole; 5-Chloro-2-. { 5-Chloro-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -6-fluoro-1H-benzoimidazole; 5-fer-Butl-2-. { 5-chloro-2- [4- (1-methyl-p -peridin-4-yl) -butoxy] -pyridin-4-ii} -1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-p-peridin-4-yl) -butoxy] -pyridin-4-yl} -4-chloro-1 H-benzoimidazole; 2-. { 5-Bromo-2- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-6-fluoro-1 H-benzoimidazole; 2-. { 5-Bromo-2-. { 4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-4-yl} -5-chloro-1 H-benzoimidazole; Y . { 4- (4,6-Dimethyl-1H-benzoimidazol-2-yl) -6- [4- (1-methyl-piperidin-4-yl) -butoxy] -pyridin-3-yl} -metanoi. 31.- A pharmaceutical composition for treating or preventing a condition mediated by H 4 receptor in a subject, comprising at least one H receptor modulator selected from compounds described in claim 1. 32.- A pharmaceutical composition for treating or preventing a condition mediated by H 4 receptor in a subject, comprising at least one H 4 receptor modulator selected from compounds described in claim 2. 33.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least one H receptor modulator selected from compounds described in claim 3. 34.- A pharmaceutical composition for treating or preventing a condition mediated by H receptor in a subject, comprising at least one H4 receptor modulator selected from compounds that are described in claim 4. 35.- A pharmaceutical composition A method for treating or preventing a condition mediated by a H 4 receptor in a subject, comprising at least one H 4 receptor modulator selected from compounds described in claim 5. 36.- A pharmaceutical composition for treating or preventing a condition receptor-mediated H4 in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 6. 37.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds that are described in claim 7. 38.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, which comprises at least one H4 receptor modulator selected from compounds that are described in claim 8. 39.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 9. 40.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least one H4 receptor modulator selected from Compounds that are described in claim 10. 41.- A pharmaceutical composition for treating or preventing a condition mediated by a H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in the claim 11. 42.- A pharmaceutical composition for treating or preventing a condition mediated by a H4 receptor in a subject, which comprises at least an H4 receptor modulator selected from compounds described in claim 12. 43.- A pharmaceutical composition for treating or preventing a condition mediated by a H4 receptor in a subject, comprising at least one H4 receptor modulator. 44. A pharmaceutical composition for treating or preventing an H receptor-mediated condition in a subject, comprising at least one H receptor modulator selected from compounds that are described in FIG. the reinvidication. 14 45. - A pharmaceutical composition for treating or preventing a condition mediated by H 4 receptor in a subject, comprising at least one H 4 receptor modulator selected from compounds described in claim 15. 46.- A pharmaceutical composition for treating or to prevent a condition mediated by a H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 16. 47.- A pharmaceutical composition for treating or preventing a condition mediated by a receptor of H4. H4 in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 17. 48.- A pharmaceutical composition for treating or preventing a condition mediated by H receptor in a subject, comprising at least one H receptor modulator selected from compounds that are described in claim 18. 49.- A pharmaceutical composition A method for treating or preventing a condition mediated by a H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 19. 50.- A pharmaceutical composition for treating or preventing a condition H4 receptor mediated in a subject, comprising at least one H receptor modulator selected from compounds described in claim 20. 51.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 21. 52. A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least an H4 receptor modulator selected from compounds that are described in claim 22. 53.- A pharmaceutical composition for treating or pre-treating come a condition mediated by a H4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 23. 54.- A pharmaceutical composition for treating or preventing a condition mediated by a receptor. H in a subject, comprising at least one H 4 receptor modulator selected from compounds described in claim 24. 55.- A pharmaceutical composition for treating or preventing a condition mediated by H 4 receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 25. 56.- A pharmaceutical composition for treating or preventing a condition mediated by H4 receptor in a subject, comprising at least one receptor modulator. of H selected from compounds that are described in claim 26. 57.- A pharmaceutical composition for treating or preventing a medi by a H receptor in a subject, comprising at least one H receptor modulator selected from compounds described in claim 27. 58.- A pharmaceutical composition for treating or preventing a condition mediated by H receptor in a subject, comprising at least one H4 receptor modulator selected from compounds described in claim 28. 59. A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one inhibitor of recruitment of leukocytes selected from compounds that are described in claim 1. 60.- A pharmaceutical composition for inhibiting leukocyte recruitment in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 2. 61.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 3. 62.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 4. 63.- A pharmaceutical composition for inhibiting leukocyte recruitment in a subject, comprising at least one leukocyte recruitment inhibitor. 64.- A pharmaceutical composition for inhibiting leukocyte recruitment in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in Claim 6. A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 7. 66.- A pharmaceutical composition for inhibiting the recruitment of leukocytes into a subject, comprising at least one recruitment inhibitor d and leukocytes selected from compounds described in claim 8. 67.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 9. . 68. - A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 10. 69.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 11. 70. A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one inhibitor of recruitment of leukocytes. leukocytes selected from compounds described in claim 12. 71.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 13. 72.- A pharmaceutical composition to inhibit the recruit A leukocyte composition in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 14. 73. A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least a leukocyte recruitment inhibitor selected from compounds described in claim 15. 74.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds that are described in claim 16. 75.- A pharmaceutical composition for inhibiting the leukocyte recruitment in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 17. 76.- A pharmaceutical composition for inhibit the recruitment of leukocytes in a subject, which comprises minus a leukocyte recruitment inhibitor selected from compounds described in claim 18. 77.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds that are described in claim 19. 78.- A pharmaceutical composition for inhibiting the leukocyte recruitment in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 20. 79.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 21. 80.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one selective leukocyte recruitment inhibitor The invention relates to a pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds that are described in claim 23. A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 24. 83.- A pharmaceutical composition for inhibiting the recruitment of leukocytes into a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 25. 84.- A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one recruitment inhibitor. of leukocytes selected from compounds described in claim 26. 26. A pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject, comprising at least one leukocyte recruitment inhibitor selected from compounds described in claim 27. 86.- A pharmaceutical composition for inhibiting leukocyte recruitment in a subject, comprising at least one leukocyte recruitment inhibitor. Selected from compounds that are described in claim 28. 87. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 1. 88. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 2. 89.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 3. 90.- An anti-inflammatory composition, comprising at least one anti-inflammatory composition. less an anti-inflammatory compound selected from compue These are described in claim 4. 91.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 5. 92.- An amphiinflammatory composition, comprising at least one anti-inflammatory compound Selected from compounds that are described in claim 6. 93. An anti-inflammatory composition, comprising at least one amphi-inflammatory compound selected from compounds that are described in claim 7. 94. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 8. 95.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 9. 96.- An anti-inflammatory composition, comprising at least one anti-inflammatory composition. less an anti-inflammatory compound selected from The compositions described in claim 10. 97.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 11. 98.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound. selected from compounds that are described in claim 12. 99.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in claim 13. 100. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in claim 14. 101. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 15. 102.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in claim 16. 103.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in the claim 17. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 18. 105. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in the claim 19. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 20. 107. An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in claim 21. 108.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in claim 22. 109.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that they are described in claim 23. 110.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 24. 111.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected. of compounds that are described in claim 25. 112.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds described in claim 26. 113.- An anti-inflammatory composition, comprising at least one anti-inflammatory compound selected from compounds that are described in claim 27. 114. An anti-inflammatory composition, comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds described in claim 28. 115. - The use of at least one anti-inflammatory compound selected from compounds described in claim 1, for the preparation of a pharmaceutical composition for treating or preventing inflammation in a subject with respect to an inflammatory response. 116. The use claimed in claim 115, wherein said inflammatory response is a response to at least one of the conditions: inflammatory disorders, allergic disorders, dermatological disorders, autoimmune diseases, lymphatic disorders, itching of the skin and Immunodeficiency disorders. 117. The use claimed in claim 115, wherein said inflammatory response is a response to chemotherapy. 118. The use claimed in claim 115, wherein said inflammatory response is a response to at least one of a response to a physical stimulus and a response to a chemical stimulus. 119.- The use claimed in claim 115, wherein said inflammatory response is a response to infection. 120. The use claimed in claim 115, wherein said inflammatory response is a response to an invasion by a body that is foreign to said subject. 121. The use claimed in claim 115, wherein said inflammatory response is a response to an immunological stimulus. 122. The use claimed in claim 115, wherein said inflammatory response is a response to at least one of the conditions: allergy, asthma, chronic obstructive pulmonary disease (COPD), aferosclerosis, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. 123. The use claimed in claim 122, wherein said inflammatory bowel disease is at least one of Crohn's disease and ulcerative colitis. 124. The use claimed in claim 115, wherein said inflammatory response is a response to at least one of psoriasis, allergic rhinitis, scleroderma, autoimmune thyroid disease, immune-mediated diabetes mellitus, and lupus. 125. The use claimed in claim 115, wherein said inflammatory response is a response to at least one of the conditions: myasthenia gravis, autoimmune neuropathy. 126. The use claimed in claim 125, wherein said autoimmune neuropathy is Guillain-Barré neuropathy. 127.- The use claimed in claim 115, wherein said inflammatory response is a response to at least one of the conditions: autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome and vasculitis. 128. The use claimed in claim 127, wherein said vasculitis is Wegener's granulomatosis. 129.- The use claimed in claim 115, wherein said inflammatory response is a response to at least one of the conditions: Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, primary biliary cirrhosis, autoimmune hepatitis, oophoritis autoimmune, autoimmune orchitis, autoimmune disease of the adrenal gland, polymyositis, dermatomyositis, spondyloarthropathy. 130. The use claimed in claim 129, wherein said spondyloarthropathy is ankylosing spondylitis. 131. The use claimed in claim 115, wherein said inflammatory response is a response to at least Sjogren's syndrome. 132. The use claimed in claim 115, wherein said inflammatory response is at least one of acute inflammation.; allergic inflammation; and chronic inflammation. 133. The use of at least one H4 receptor modulator selected from compounds that are described in claim 1, for the preparation of a pharmaceutical composition for treating or preventing an H4 mediated condition in a subject. 134. A method for modulating an H4 receptor, comprising exposing an H4 receptor to at least one selected modulator of compounds that are described in claim 1. 135. The method according to claim 134, further characterized because said modulator is an H 4 receptor antagonist. 136. - The method according to claim 134, further characterized in that said modulator is a partial agonist of H4 receptor. The use of at least one leukocyte recruitment inhibitor selected from compounds that are described in claim 1, for the preparation of a pharmaceutical composition for inhibiting the recruitment of leukocytes in a subject.